Imidazo(4,5-b) pyridin-2-yl amides as kv7 channel activators

ABSTRACT

Compounds represented by formula 1 can be potent and/or partially selective for the Kv7.2/7.3 heteromultimer. They may be useful in treating disorders related to seizures, pain, neurotransmitter release, etc.

BACKGROUND

Potassium (K⁺) channels, present on the plasma membranes of most cell types, are the most diverse class of all ion channels and are associated with a wide range of physiological functions including the regulation of the electrical properties of excitable cells. The primary pore-forming (a) subunits of these highly selective cation channels are divided into three primary structural classes based on the number of transmembrane (TM)-spanning regions and pore (P) regions: currently there are known to be 6TM/1P, 2TM/1P and 4TM/2P K⁺ channels. The K_(V)7 genes (originally termed KCNQ, a name assigned by the HUGO Gene Nomenclature Committee (HGNC) were assigned to a subfamily of voltage-gated K⁺ channels by the International Union of Pharmacology (IUPHAR). The K_(V)7 subfamily consists of five homologous pore-forming α subunits, K_(V)7.1-7.5, that have a structure typical of voltage-gated K⁺ channels with 6TM-spanning regions (S1-S6) flanked by intracellular N-terminal and C-terminal domains, a typical voltage-sensor domain located in S4 comprised of alternating positively-charged residues and a single P region between S5 and S6 of each subunit. The channels are formed as tetramers of the primary α subunits, either as homotetramers or heterotetramers. Neurons are known to express K_(V)7 channels comprised of K_(V)7.2-7.5 α subunits. Some of these gene products may be exclusively neuronal while others, such as K_(V)7.4 and K_(V)7.5, can be found in other tissues such as smooth and skeletal muscle.

Native M-channels, and the corresponding macroscopic M-current, were first characterized in amphibian sympathetic neurons. M-channels were notable because they were slowly activating and non-inactivating, active at membrane potentials at or near the resting membrane potential of neurons and muscarinic cholinergic agonists produced a reduction in the M-current, demonstrating a direct and inhibitory link between G-protein coupled receptors (GPCRs) and a physiological K⁺ current. It was not until the cloning of this subfamily of genes that the pharmacological and biophysical identity was established between K_(V)7.2/7.3 (and likely K_(V)7.5/7.3) heteromultimers and the elusive ‘M’-channel, providing significant new evidence for their importance in neuronal regulation.

The distributions of these channels, both regionally and developmentally, as well as their biophysical characteristics, support their role in providing enduring resistance to depolarizing excitatory influences. Under physiological conditions, as was demonstrated with native M-channels, they can be very effective at regulating the sub-threshold excitability of certain neuronal populations with significant roles in regulating the frequency and ultimately the pattern of action potential discharge in many types of neurons. Their importance in neuronal regulation was punctuated by the discovery that neuronal K_(V)7 mutations lead to benign familial neonatal convulsions (BFNC) indicating that reduction or removal of the influence of K_(V)7.2 and K_(V)7.3 channels can dramatically alter neuronal excitability. Mutation analyses demonstrated their involvement in BFNC and suggested their utility as targets for anti-epileptic drugs (AEDs).

Unlike established pharmacological terminology for GPCRs, the mode of action of K⁺ channel modulators, in particular compounds that activate the channel, is still being refined. The application of voltage-clamp techniques to the study of ion channel pharmacology enabled detailed biophysical studies on either whole-cell currents or single channels, allowing some characterization of the nature of compound-channel interactions but not preventing ongoing confusion around the terminology. The term opener or activator is commonly used throughout the literature but does not adequately describe the mode of action of all these ‘positive modulator’ compounds. In general, openers or activators are expected to increase the open probability of the channel or increase macroscopic current amplitude, but this nomenclature is really too simplistic. For example, retigabine, the first publicly disclosed K_(V)7 opener, has a complex and interesting profile in that it has inhibitory activity at higher membrane potentials. Neuronal K_(V)7 channel openers may work in concert with the activity of a channel over the ‘normal’ activation-voltage range and enhance currents without significantly affecting the activation threshold while others can significantly alter the activation threshold. In addition, some openers appear to remove the voltage-dependence of activation entirely. Whether these effects represent some continuum is currently unclear since the effects are often concentration-dependent. Clearly, the modes of interaction of compounds that can increase channel current are complex and in most cases not well understood and the implications of these profiles on neuronal responsiveness and systems physiology are also unclear. Retigabine is modestly potent, not highly specific, but it is a very effective opener of K_(V)7.2, K_(V)7.5 and heteromultimeric K_(V)7 channels. Its effects are characterized by a significant increase in channel current over a narrow voltage range. As mentioned above, at more positive voltages the opener is less effective and under some conditions channel current significantly decreases at more positive voltages relative to control currents (this ‘crossover’ voltage-dependence of opener action is a characteristic of many neuronal K_(V)7 channel openers). This effect is also concentration-dependent and is more pronounced at higher concentrations.

SUMMARY

Described herein are compounds that can be potent and/or at least partially selective for the K_(V)7.2/7.3 heteromultimer. These compounds may have reduced untoward side effects as compared to retigabine.

Some embodiments include a compound represented by Formula 1:

wherein A is optionally substituted 1H-imidazo[4,5-b]pyridin-2-yl or optionally substituted 3H-imidazo[4,5-b]pyridin-2-yl; L is CH₂, CF₂, C₂H₄, C₃H₆, O, CH₂O, C₂H₄O, or C₃H₆O; and R¹ is C₁₋₁₂ optionally substituted alkyl, C₁₋₁₂ optionally substituted —O-alkyl, optionally substituted C₆₋₁₀ aryl, optionally the compound is active at a K_(V)7.2 bearing potassium channel, a K_(V)7.3 bearing potassium channel, a K_(V)7.4 bearing potassium channel, or a K_(V)7.5 bearing potassium channel.

In some embodiments, A is optionally substituted 1H-imidazo[4,5-b]pyridin-2-yl or optionally substituted 3H-imidazo[4,5-b]pyridin-2-yl; L is CH₂, CF₂, C₂H₄, C₃H₆, O, CH₂O, C₂H₄O, or C₃H₆O; and R¹ is CH₃, C₂₋₁₂ optionally substituted alkyl, C₁₋₁₂ optionally substituted —O-alkyl, optionally substituted C₆₋₁₀ aryl, optionally substituted C₆₋₁₀—O-aryl, or optionally substituted C₂₋₉ heterocyclyl.

Some embodiments include a composition comprising a compound described herein, wherein the composition is pharmaceutically acceptable.

Some embodiments include a pharmaceutical dosage form comprising a compound described herein.

Some embodiments include a method of treating a disorder associated with a K_(V)7 potassium channel activator comprising administering an effective amount of a compound described herein.

DETAILED DESCRIPTION

Unless otherwise indicated, when a compound or chemical structural feature such as aryl is referred to as being “optionally substituted,” it includes a feature that has no substituents (i.e. unsubstituted), or a feature that is “substituted,” meaning that the feature has one or more substituents. The term “substituent” has the broadest meaning known to one of ordinary skill in the art, and includes a moiety that replaces one or more hydrogen atoms attached to a parent compound or structural feature. In some embodiments, a substituent may be an ordinary organic moiety known in the art, which may have a molecular weight (e.g. the sum of the atomic masses of the atoms of the substituent) of 15 g/mol to 50 g/mol, 15 g/mol to 100 g/mol, 15 g/mol to 150 g/mol, 15 g/mol to 200 g/mol, 15 g/mol to 300 g/mol, or 15 g/mol to 500 g/mol. In some embodiments, a substituent comprises, or consists of: 0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0-10, or 0-5 heteroatoms, wherein each heteroatom may independently be: N, O, S, Si, F, Cl, Br, or I; provided that the substituent includes one C, N, O, S, Si, F, Cl, Br, or I atom. Examples of substituents include, but are not limited to, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, etc.

For convenience, the term “molecular weight” is used with respect to a moiety or part of a molecule to indicate the sum of the atomic masses of the atoms in the moiety or part of a molecule, even though it may not be a complete molecule.

The structures associated with some of the chemical names referred to herein are depicted below. These structures may be unsubstituted, as shown below, or a substituent may independently be in any position normally occupied by a hydrogen atom when the structure is unsubstituted. Unless a point of attachment is indicated by

, attachment may occur at any position normally occupied by a hydrogen atom.

As used herein, the term “alkyl” has the broadest meaning generally understood in the art, and may include a moiety composed of carbon and hydrogen containing no double or triple bonds. Alkyl may be linear alkyl, branched alkyl, cycloalkyl, or a combination thereof, and in some embodiments, may contain from one to thirty-five carbon atoms. In some embodiments, alkyl may include C₁₋₁₀ linear alkyl, such as methyl (—CH₃), ethyl (—CH₂CH₃), n-propyl (—CH₂CH₂CH₃), n-butyl (—CH₂CH₂CH₂CH₃), n-pentyl (—CH₂CH₂CH₂CH₂CH₃), n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), etc.; C₃₋₁₀ branched alkyl, such as C₃H₇ (e.g. iso-propyl), C₄H₉ (e.g. branched butyl isomers), C₅H₁₁ (e.g. branched pentyl isomers), C₆H₁₃ (e.g. branched hexyl isomers), C₇H₁₅ (e.g. heptyl isomers), etc.; C₃₋₁₀ cycloalkyl, such as C₃H₅ (e.g. cyclopropyl), C₄H₇ (e.g. cyclobutyl isomers such as cyclobutyl, methylcyclopropyl, etc.), C₅H₉ (e.g. cyclopentyl isomers such as cyclopentyl, methylcyclobutyl, dimethylcyclopropyl, etc.) C₆H₁₁ (e.g. cyclohexyl isomers), C₇H₁₃ (e.g. cycloheptyl isomers), etc.; and the like.

With respect to an optionally substituted moiety such as optionally substituted alkyl, a phrase such as “optionally substituted C₁₋₁₂ alkyl” refers to a C₁₋₁₂ alkyl that may be unsubstituted, or may have 1 or more substituents, and does not limit the number of carbon atoms in any substituent. Thus, for example, CH₂(CH₂)₁₁OCH₃ is optionally substituted C₁₋₁₂ alkyl because the parent alkyl group has 12 carbon atoms. A phrase such as “C₁₋₁₂ optionally substituted alkyl” refers to unsubstituted C₁₋₁₂ alkyl, or substituted alkyl wherein the alkyl parent and all substituents together have from 1-12 carbon atoms. For example, CH₂CH₂OCH₃ is C₁₋₁₂ optionally substituted alkyl because the alkyl group (e.g. ethyl) and the substituent (e.g. methoxy) together contain 3 carbon atoms. Similar conventions may be applied to other optionally substituted moieties such as aryl and heterocyclyl.

Substituents on alkyl may be the same as those described generally above. In some embodiments, substituents on alkyl are independently selected from F, Cl, Br, I, CN, CO₂H, —O-alkyl, ester groups, acyl, amine groups, amide groups, phenyl (including fused phenyl resulting optionally substituted alkyl such as indenyl, where the phenyl substituent is fused to the parent alkyl moiety), and may have a molecular weight of about 15 to about 100 or about 500.

As used herein the term “aryl” has the broadest meaning generally understood in the art, and may include an aromatic ring or aromatic ring system such as phenyl, naphthyl, etc.

The term “heterocyclyl” includes any ring or ring system containing a heteroatom such as N, O, S, P, etc. Heterocyclyl includes heteroaryl rings or ring systems (such as those listed below) and non-aromatic rings or ring systems. Examples of non-aromatic heterocyclyl include azetidinyl, oxatanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxalanyl, dithiolanyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino, etc.

The term “heteroaryl” also has the meaning understood by a person of ordinary skill in the art, and includes an “aryl” which has one or more heteroatoms in the ring or ring system, such as pyridinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, oxadiazolyl, isoxazolyl, indolyl, quinolinyl, benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl, benzoimidazolyl, etc.

Unless otherwise indicated, any reference to a compound herein by structure, name, or any other means, includes pharmaceutically acceptable salts, such as HCl, HBr, HI, H₂SO₄, acetate, citrate, sodium, potassium, and ammonium salts; prodrugs, such as ester prodrugs; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described.

If stereochemistry is not indicated, a name or structural representation includes any stereoisomer or any mixture of stereoisomers.

With respect to any relevant formula or structural representation herein, such as Formula 1, A is optionally substituted imidazo[4,5-b]pyridin-2-yl, such as optionally substituted 1H-imidazo[4,5-b]pyridin-2-yl or optionally substituted 3H-imidazo[4,5-b]pyridin-2-yl. If the imidazo[4,5-b]pyridin-2-yl is substituted, it may have 1, 2, 3, or 4 substituents. Any substituent may be included on the imidazo[4,5-b]pyridin-2-yl. In some embodiments, some or all of the substituents on the imidazo[4,5-b]pyridin-2-yl may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I (provided that there is at least 1 non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500 g/mol. For example, the substituents may be C₁₋₁₀ optionally substituted alkyl, such as CH₃, C₂H₅, CO₃H₇, cyclic C₃H₅, C₄H₉, cyclic C₄H₇, C₅H₁₁, cyclic C₅H₉, C₆H₁₃, cyclic C₆H₁₁, etc., which may be optionally substituted; C₁₋₁₀ optionally substituted alkoxy such as OCH₃, OC₂H₅, OC₃H₇, cyclic OC₃H₅, OC₄H₉, cyclic OC₄H₇, OC₅H₁₁, cyclic OC₅H₉, OC₆H₁₃, cyclic OC₆H₁₁, etc.; halo, such as F, Cl, Br, I; OH; CN; NO₂; C₁₋₆ fluoroalkyl, such as CF₃, CF₂H, C₂F₅, etc.; C₁₋₆ fluoroalkoxy, such as OCF₃, OCF₂H, OC₂F₅, etc.; a C₁₋₁₀ ester such as —O₂CCH₃, —CO₂CH₃, —O₂CC₂H₅, —CO₂C₂H₅, —O₂C-phenyl, —CO₂-phenyl, etc.; a C₁₋₁₀ ketone such as —COCH₃, —COC₂H₅, —COC₃H₇, —CO-phenyl, etc.; or a C₁₋₁₀ amine such as NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)C₂H₅, etc.

In some embodiments, any or all of the substituents of 1H-imidazo[4,5-b]pyridin-2-yl or 3H-imidazo[4,5-b]pyridin-2-yl are independently CF₃, Cl, CN, or OCH₃. In some embodiments, A has a CF₃ substituent. In some embodiments, A has a Cl substituent. In some embodiments, A has a CN substituent. In some embodiments, A has an OCH₃ substituent.

In some embodiments, A may be:

Some embodiments may include a compound represented by one or more of Formulas 2-45.

With respect to any relevant formula or structural representation herein, such as Formulas 1-41, L is CH₂, CF₂, C₂H₄ (such as CH₂CH₂, CH(CH₃), etc.), C₃H₆ (such as CH₂CH₂CH₂, CH₂CH(CH₃), CH(CH₃)CH₂, CH(CH₃)₂, etc.), O, CH₂O, C₂H₄₀ (such as OCH₂CH₂ (where the O atom may be on either side of the CH₂CH₂), CH₂OCH₂, OCH(CH₃), etc.,), or C₃H₆O.

In some embodiments, L is CH₂, CF₂, CH₂CH₂, CH(CH₃)₂, or C(CH₃).

In some embodiments, L is CH₂.

In some embodiments, L is CH₂CH₂.

In some embodiments, L is C(CH₃)₂.

In some embodiments, L is CH(CH₃).

In some embodiments, L is CH₂CH(CH₃).

With respect to any relevant formula or structural representation herein, such as Formulas 1-5, R¹ may be C₁₋₁₂ optionally substituted alkyl, such as optionally substituted CH₃, optionally substituted C₂H₅, optionally substituted C₃H₇, optionally substituted cyclic C₃H₅, optionally substituted C₄H₉, optionally substituted cyclic C₄H₇, optionally substituted C₅H₁₁, optionally substituted cyclic C₅H₉, optionally substituted C₆H₁₃, optionally substituted cyclic C₆H₁₁, optionally substituted bicyclo[2.2.1]heptan-2-yl, optionally substituted bicyclo[3.1.1]heptan-2-yl, etc.; C₁₋₁₂ optionally substituted —O— alkyl, such as optionally substituted —O—CH₃, optionally substituted —O—C₂H₅, optionally substituted —O—C₃H₇, optionally substituted cyclic —O—C₃H₅, optionally substituted —O—C₄H₉, optionally substituted cyclic —O—C₄H₇, optionally substituted —O—C₅H₁₁, optionally substituted cyclic —O—C₅H₉, optionally substituted —O—C₆H₁₃, optionally substituted cyclic —O—C₆H₁₁, optionally substituted (2,3-dihydro-1H-inden-1-yl)oxy, etc.; optionally substituted C₆₋₁₀ aryl, such as optionally substituted phenyl; optionally substituted C₆₋₁₀—O-aryl, such as optionally substituted —O-phenyl; or optionally substituted C₂₋₉ heterocyclyl, such as optionally substituted isoxazolyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuryanyl, etc. In some embodiments, R¹ is CH₃, C₂₋₁₂ optionally substituted alkyl, C₁₋₁₂ optionally substituted —O-alkyl, optionally substituted C₆₋₁₀ aryl, optionally substituted C₆₋₁₀—O-aryl, or optionally substituted C₂₋₉ heterocyclyl.

With respect to any relevant formula or structural representation herein, such as Formulas 1-5, in some embodiments, R¹ is optionally substituted phenyl. In some embodiments, R¹ is C₃₋₄ alkyl. In some embodiments, R¹ is optionally substituted pyridinyl. In some embodiments, R¹ is optionally substituted bicyclo[2.2.1]heptan-2-yl. In some embodiments, R¹ is optionally substituted isoxazol-3-yl. In some embodiments, R¹ is CF₃. In some embodiments, R¹ is optionally substituted cyclopentyl. In some embodiments, R¹ is optionally substituted cyclohexyl. In some embodiments, R¹ is methyl. In some embodiments, R¹ is optionally substituted bicyclo[3.1.1]heptan-2-yl. In some embodiments, R¹ is optionally substituted —O-phenyl. In some embodiments, R¹ is optionally substituted CH(CF₃)₂. In some embodiments, R¹ is C₂₋₄—O-alkyl. In some embodiments, R¹ is optionally substituted adamantan-1-yl. In some embodiments, R¹ is optionally substituted tetrahydro-2H-pyranyl. In some embodiments, R¹ is optionally substituted (2,3-dihydro-1H-inden-1-yl)oxy. In some embodiments, R¹ is optionally substituted tetrahydrofuranyl. In some embodiments, R¹ is optionally substituted thiazolyl. In some embodiments, R¹ is optionally substituted 2-oxabicyclo[3.2.0]heptanyl

With respect to any relevant formula or structural representation herein, such as Formulas 1-5:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is CH₃. In some embodiments, R¹ is CF₃.

In some embodiments, R¹ is CH(CF₃)₂.

In some embodiments, R¹ is CH₂CH₂R³⁴.

In some embodiments, R¹ is —OCH₂CH₂R³⁴.

In some embodiments, R¹ is —OCH₂-cyclopropyl.

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is optionally substituted cyclopropyl.

In some embodiments, R¹ is optionally substituted spiro[3.3]heptanyl.

In some embodiments, R¹ is CH₂OCH₃.

With respect to any relevant formula or structural representation herein, such as Formulas 2 and 5-41, R² is —R^(a)-Cy. R^(a) is a bond or C₁₋₁₂ optionally substituted alkyl, such as CH₂, C₂H₄, C₃H₆, C₄H₈, C₅H₁₀, C₆H₁₂, cyclic C₃H₅, cyclic C₄H₇, cyclic C₅H₉, cyclic C₆H₁₁, etc. Cy is H; optionally substituted C₆₋₁₀ aryl, such as optionally substituted phenyl; or optionally substituted C₂₋₉ heterocyclyl, such as optionally substituted azetidinyl, optionally substituted oxatanyl, optionally substituted thietanyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, optionally substituted furyl, optionally substituted thienyl, etc. In some embodiments, R² is optionally substituted cyclobutyl (such as difluorocyclobutyl, tetrafluorocyclobutyl, etc.) or optionally substituted 2-methylpropyl.

In some embodiments, R² is:

In some embodiments, R² is:

In some embodiments, R² is:

With respect to any relevant formula or structural representation herein, such as Formulas 2 and 5-41, in some embodiments, R² is cyclobutyl. In some embodiments, R² is 2-methylpropyl. In some embodiments, R² is —CH₂CH═CH₂. In some embodiments, R² is —CH₂CF₃. In some embodiments, R² is t-butyl. In some embodiments, R² is n-propyl. In some embodiments, R² is 4-fluorophenyl. In some embodiments, R² is optionally substituted isoxazol-3-yl. In some embodiments, R² is optionally substituted pyridinyl. In some embodiments, R² is optionally substituted triazolyl. In some embodiments, R² is optionally substituted oxadiazolyl. In some embodiments, R² is optionally substituted isoxazolyl.

In some embodiments, R² is

Generally R³-R⁵², may be H or any substituent, such as a substituent having 0 to 12 atoms or 0 to 6 carbon atoms and 0 to 5 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I, and/or having a molecular weight of 15 g/mol to 300 g/mol. Any of R³-R⁵² may comprise: a) 1 or more alkyl moieties optionally substituted with, or optionally connected by or to, b) 1 or more functional groups, such as C═C, C≡C, CO, CO₂, CON, NCO₂, OH, SH, O, S, N, N═C, F, Cl, Br, I, CN, NO₂, CO₂H, NH₂, etc.; or may be a substituent having no alkyl portion, such as F, Cl, Br, I, NO₂, CN, NH₂, OH, COH, CO₂H, etc.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R³ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R³ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers (e.g. n-propyl and isopropyl), cyclopropyl, butyl isomers, cyclobutyl isomers (e.g. cyclobutyl and methylcyclopropyl), pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O— cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³ may be H, F, Cl, Br, I, CN, C₁₋₁₂ optionally substituted alkyl, C₁₋₁₂ optionally substituted —O-alkyl, optionally substituted C₂₋₉ heterocyclyl, optionally substituted C₆₋₁₀ aryl, optionally substituted C₂₋₉—O-heterocyclyl, optionally substituted C₆₋₁₀—O-aryl, C₁₋₁₂ optionally substituted acylamino, C₁₋₁₂ optionally substituted aminoacyl, or optionally substituted C₁₋₁₂ aminoalkyl (or alkyl with an amino substituent). In some embodiments, R³ may be H, CH₃, OH, OCH₃, NH₂, NHCH₃, N(CH₃)₂, COH, COCH₃, CF₃, Cl, CN, or OCH₃. In some embodiments, R³ may be H, CF₃, Cl, CN, or OCH₃. In some embodiments, R³ is H. In some embodiments, R³ is CF₃. In some embodiments, R³ is Cl. In some embodiments, R³ is CN. In some embodiments, R³ is OCH₃.

Each R^(A) may independently be H, or C₁₋₁₂ alkyl, including: linear or branched alkyl having a formula C_(a)H_(a+1), or cycloalkyl having a formula C_(a)H_(a−1), wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl of a formula: CH₃, C₂H₅, C₃H₇, C₄H₉, C₅H₁₁, C₆H₁₃, C₇H₁₅, C₈H₁₇, C₉H₁₉, C₁₀H₂₁, etc., or cycloalkyl of a formula: C₃H₅, C₄H₇, C₅H₉, C₆H₁₁, C₇H₁₃, C₈H₁₅, CC₉H₁₇, C₁₀H₁₉, etc. In some embodiments, R^(A) may be H or C₁₋₆ alkyl. In some embodiments, R^(A) may be H or C₁₋₃ alkyl. In some embodiments, R^(A) may be H or CH₃. In some embodiments, R^(A) may be H.

Each R^(B) may independently be H, or C₁₋₁₂ alkyl, including: linear or branched alkyl having a formula C_(a)H_(a+1), or cycloalkyl having a formula C_(a)H_(a), wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl of a formula: CH₃, C₂H₅, C₃H₇, C₄H₉, C₅H₁₁, C₆H₁₃, C₈H₁₇, C₇H₁₅, C₉H₁₉, C₁₀H₂₁, etc., or cycloalkyl of a formula: C₃H₅, C₄H₇, C₅H₉, C₆H₁₁, C₇H₁₃, C₈H₁₅, CC₉H₁₇, C₁₀H₁₉, etc. In some embodiments, R^(B) may be H or C₁₋₃ alkyl. In some embodiments, R^(B) may be H or CH₃. In some embodiments, R^(B) may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁴ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁴ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc., or —O—C₁₋₆ alkyl, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴ may be H, F, Cl, Br, I, CN, C₁₋₁₂ optionally substituted alkyl, C₁₋₁₂ optionally substituted —O-alkyl, optionally substituted C₂₋₉ heterocyclyl, optionally substituted C₆₋₁₀ aryl, optionally substituted C₂₋₉—O-heterocyclyl, optionally substituted C₆₋₁₀—O-aryl, C₁₋₁₂ optionally substituted acylamino, C₁₋₁₂ optionally substituted aminoacyl, or optionally substituted C₁₋₁₂ aminoalkyl. In some embodiments, R⁴ may be H, CF₃, or Cl. In some embodiments, R⁴ is H. In some embodiments, R⁴ is CF₃. In some embodiments, R⁴ is Cl. In some embodiments, R⁴ is CN. In some embodiments, R⁴ is OCH₃.

With respect to any relevant structural representation herein, in some embodiments, R³ is CF₃ and R⁴ is Cl.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁵ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁵ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁵ may be H, F, Cl, Br, I, CN, C₁₋₁₂ optionally substituted alkyl, C₁₋₁₂ optionally substituted —O-alkyl, optionally substituted C₂₋₉ heterocyclyl, optionally substituted C₆₋₁₀ aryl, optionally substituted C₂₋₉—O-heterocyclyl, optionally substituted C₆₋₁₀—O-aryl, C₁₋₁₂ optionally substituted acylamino, C₁₋₁₂ optionally substituted aminoacyl, or optionally substituted C₁₋₁₂ aminoalkyl. In some embodiments, R⁵ may be H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁵ may be H. In some embodiments, R⁵ may be CH₃.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁶ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁶ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁶ may be H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁶ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁷ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁷ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁷ may be H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁷ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁸ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁸ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁸ may be H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁸ is H. In some embodiments, R⁸ is F.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁹ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁹ may be H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁹ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R¹⁰ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R¹⁰ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹⁰ may be H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R¹⁰ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R¹¹ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R¹¹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹¹ is H, CH₃, F, Cl, or CF₃. In some embodiments, R¹¹ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R¹² may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R¹² may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹² is H, CH₃, F, Cl, or CF₃. In some embodiments, R¹² may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R¹³ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R¹³ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹³ is H, CH₃, F, Cl, or CF₃. In some embodiments, R¹³ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R¹⁴ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R¹⁴ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹⁴ is H, CH₃, F, Cl, or CF₃. In some embodiments, R¹⁴ may be H. In some embodiments, R¹⁴ may be F.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R¹⁵ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R¹⁵ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹⁵ is H, CH₃, F, Cl, or CF₃. In some embodiments, R¹⁵ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R¹⁶ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R¹⁶ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹⁶ is H, CH₃, F, Cl, or CF₃. In some embodiments, R¹⁶ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R¹⁷ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R¹⁷ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹⁷ is H, CH₃, F, Cl, or CF₃. In some embodiments, R¹⁷ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R¹⁸ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R¹⁸ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹⁸ may be H, F, Cl, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In some embodiments, R¹⁸ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R¹⁹ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R¹⁹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R¹⁹ may be H, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In some embodiments, R¹⁹ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R²⁰ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R²⁰ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²⁰ may be H, F, Cl, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In some embodiments, R²⁰ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R²¹ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R²¹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²¹ may be H, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In some embodiments, R²¹ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R²² may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R²² may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²² may be H, F, Cl, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In some embodiments, R²² may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R²³ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R²³ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²³ may be H, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In some embodiments, R²³ is H. In some embodiments, R²³ is CH₃.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R²⁴ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R²⁴ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²⁴ may be H, F, Cl, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In some embodiments, R²⁴ is H. In some embodiments, R²⁴ is CH₃.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R²⁵ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R²⁵ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²⁵ may be H, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In some embodiments, R²⁵ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R²⁶ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R²⁶ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²⁶ may be H, F, Cl, OH, CN, CF₃, CH₃, or —OCH₃. In some embodiments, R²⁶ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R²⁷ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R²⁷ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²⁷ may be H, F, Cl, OH, CN, CF₃, CH₃, or —OCH₃. In some embodiments, R²⁷ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R²⁸ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R²⁸ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²⁸ may be H, F, CN, CF₃, or CH₃. In some embodiments, R²⁸ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R²⁹ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R²⁹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R²⁹ may be H, F, Cl, OH, CN, CF₃, CH₃, or —OCH₃. In some embodiments, R²⁹ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R³⁰ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R³⁰ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³⁰ may be H, F, Cl, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In some embodiments, R³⁰ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R³¹ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R³¹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³¹ may be H, OH, CN, CF₃, CH₃, CH₂CH₃, —OCH₃, or —OCH₂CH₃. In some embodiments, R³¹ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R³² may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R³² may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³² may be H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R³² may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R³³ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R³³ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or 01-6 alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³³ may be H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R³³ is H. In some embodiments, R³³ is CH₃.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R³⁴ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R³⁴ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³⁴ may be H, F, Cl, OH, CN, CF₃, CH₃, NH₂, NHCH₃, N(CH₃)₂, or —OCH₃. In some embodiments, R³⁴ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R³⁵ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R³⁵ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³⁵ may be H, F, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In some embodiments, R³⁵ is H. In some embodiments, R³⁵ is CH₃.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R³⁶ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R³⁶ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³⁶ may be H, F, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In some embodiments, R³⁶ is H. In some embodiments, R³⁶ is CH₃.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R³⁷ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R³⁷ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³⁷ may be H, F, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In some embodiments, R³⁷ is H. In some embodiments, R³⁷ is CH₃.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R³⁸ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R³⁸ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³⁸ may be H, F, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In some embodiments, R³⁸ is H. In some embodiments, R³⁸ is CH₃.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R³⁹ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R³⁹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R³⁹ may be H, F, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In some embodiments, R³⁹ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁴⁰ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁴⁰ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴⁰ may be H, F, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In some embodiments, R⁴⁰ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁴¹ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁴¹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴¹ may be H, F, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In some embodiments, R⁴¹ is H. In some embodiments, R⁴¹ is CH₃.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁴² may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁴² may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴² may be H, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂. In some embodiments, R⁴² is H. In some embodiments, R⁴² is CH₃.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁴³ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁴³ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴³ may be H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁴³ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁴⁴ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁴⁴ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴⁴ may be H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁴⁴ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁴⁵ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁴⁵ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴⁵ may be H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁴⁵ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁴⁶ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁴⁶ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴⁶ may be H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁴⁶ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁴⁷ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁴⁷ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴⁷ may be H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁴⁷ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁴⁸ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁴⁸ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴⁸ may be H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁴⁸ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁴⁹ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁴⁹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁴⁹ may be H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁴⁹ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁵⁰ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁵⁰ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁵⁰ may be H, F, Cl, CN, CF₃, OH; NH₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁵⁰ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁵¹ may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁵¹ may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁵¹ may be H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁵¹ may be H.

With respect to any relevant formula or structural representation herein, some non-limiting examples of R⁵² may include R^(A), F, Cl, CN, OR^(A), CF₃, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, R⁵² may be H; F; Cl; CN; CF₃; OH; NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers, pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; or C₁₋₆ alkoxy, such as —O-methyl, —O-ethyl, isomers of —O-propyl, —O-cyclopropyl, isomers of —O-butyl, isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of —O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc. In some embodiments, R⁵² may be H, F, Cl, CN, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R⁵² may be H.

Some embodiments may include one of the compounds below:

EXPERIMENTAL SECTION

Scheme 1 shows a general methodology for the synthesis of 3H-imidazo[4,5-b]pyridines such as 1.5. An appropriately substituted 2-chloro-3-nitro pyridine 1.1 is reacted with a primary amine to afford 2-amino-3-nitropyridines 1.2. The nitro group may be reduced to the corresponding amine by a variety of well-established methods to provide diaminopyridines 1.3. Reaction of 1.3 with cyanogen bromide affords 3H-imidazo[4,5-b]pyridin-2-amines 1.4. Amide coupling with either an appropriate carboxylic acid or acyl chloride can afford 3H-imidazo[4,5-b]pyridine amides such as 1.5.

Synthetic Methods Section 1. General Procedures for the Preparation of 3H-imidazo[4,5-b]pyridin-2-amine intermediates (Scheme 1) Method 1 Step A

A mixture of appropriate 2-chloro-3-nitropyridine (1 eq), amine or amine hydrochloride (1.1 eq), and triethylamine (2.5 eq) in THF (˜0.2 M) was stirred at ambient temperature until completion of reaction. The mixture was cooled to room temperature and diluted with EtOAc. The precipitated triethylamine hydrochloride was removed by filtration. The filtrate was concentrated and the residue was purified by column chromatography or by recrystallization.

Step B

To a solution of appropriate 3-nitropyridin-2-amine (3.69 mmol) in EtOH (10 mL) was added iron powder (18 mmol) and a solution of ammonium chloride (18 mmol) in water (4 mL). The mixture was heated in a microwave reactor at 140° C. for 30 min. Alternatively, the mixture was heated to reflux for 2 h. The mixture was diluted with EtOAc, filtered through Celite and concentrated to provide the title compound which was used in the next step without further purification.

Step C

To a solution of appropriate pyridine-2,3-diamine (3.5 mmol) in EtOH (17 mL) was added a solution of cyanogen bromide (3 M in CH₂Cl₂, 1.7 mL, 5.2 mmol). The mixture was stirred at room temperature for 18 h, then concentrated in-vacuo. The residue was partitioned between EtOAc and saturated aqueous NaHCO₃.

The organic layer was dried over sodium sulfate and concentrated. The residue was purified by precipitation with dichloromethane or by column chromatography.

Section 2. Procedures for the Synthesis of Intermediates for Use in Method 1, Step B or Step C for the Preparation of 2-amino-3H-imidazo[4,5-b]pyridines Method 2. 6-(Cyclobutylamino)-5-nitropicolinonitrile for Use in Method 1, Step B for Preparation of 2-amino-3-cyclobutyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile

A mixture of 6-chloro-N-cyclobutyl-3-nitropyridin-2-amine (prepared by procedure described in Method 1, Step A; 100 mg, 0.439 mmol), rac-2-(di-tert-butylphosphino)-1,1′-binaphthyl (15 mg, 0.039 mmol), zinc (0.5 mg, 8.0 μmol), zinc cyanide (29 mg, 0.25 mmol), and palladium(II) trifluoroacetate (6.3 mg, 0.019 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was purged with N₂ (g) by bubbling into the mixture for 5 min. The mixture was heated to 95° C. in a sealed vial for 18 h. The mixture was diluted with EtOAc and washed with water 5 times. The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography (0-50%, EtOAc/hexanes) to give 43 mg (45% yield) of the title compound. MS (ESI) m/z 217.2 (MH⁻).

Method 3. 6-Cyclopropyl-3-nitro-N-(2,2,2-trifluoroethyl)pyridin-2-amine for Use in Method 1, Step B for Preparation of 5-cyclopropyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-amine

To a degassed mixture of 6-chloro-3-nitro-N-(2,2,2-trifluoroethyl)pyridin-2-amine (prepared by procedure described in Method 1, Step A; 500 mg, 1.96 mmol), cyclopropylboronic acid (336 mg, 3.91 mmol), and potassium phosphate (1.2 g, 5.87 mmol) in a 9:1 mixture of THF/water (10 mL) was added palladium acetate (44 mg, 0.20 mmol) and S-Phos (161 mg, 0.390 mmol). The mixture was stirred at 100° C. for 24 h in a sealed tube, then cooled to ambient temperature and concentrated. The crude mixture was purified by column chromatography (0-20% EtOAc/hexanes) to provide 6-cyclopropyl-3-nitro-N-(2,2,2-trifluoroethyl)pyridin-2-amine (250 mg, 49%). MS (ESI) m/z 262.4 (MH⁺).

Method 4. 6-Isopropoxy-3-nitro-N-(2,2,2-trifluoroethyl)pyridin-2-amine for Use in Method 1, Step B for Preparation of 5-isopropoxy-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-amine

To a solution of 6-chloro-3-nitro-N-(2,2,2-trifluoroethyl)pyridin-2-amine (prepared by procedure described in Method 1, Step A; 500 mg, 1.96 mmol) in isopropanol (10 mL) at room temperature was added 60% sodium hydride (171 mg, 3.91 mmol). The mixture was stirred at room temperature for 4 h before it was partitioned between water (100 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with brine (2×50 mL), dried over sodium sulfate, filtered, and concentrated. The crude mixture was purified by column chromatography (0-20%, EtOAc/hexanes) to provide 6-isopropoxy-3-nitro-N-(2,2,2-trifluoroethyl)pyridin-2-amine (220 mg, 40%). MS (ESI) m/z 280.0 (MH⁺).

The following intermediates were prepared with an analogous procedure and appropriate starting materials:

-   6-(benzyloxy)-N-cyclobutyl-3-nitropyridin-2-amine -   N-cyclobutyl-3-nitro-6-(pyridin-2-ylmethoxy)pyridin-2-amine -   N-cyclobutyl-6-((1-methyl-1H-pyrazol-5-yl)methoxy)-3-nitropyridin-2-amine

Method 5. 5,6-Dichloro-3-nitro-N-(2,2,2-trifluoroethyl)pyridin-2-amine for Use in Method 1, Step B for Preparation of 5,6-dichloro-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-amine

To a solution of 6-chloro-3-nitro-N-(2,2,2-trifluoroethyl)pyridin-2-amine (prepared by procedure described in Method 1, Step A; 600 mg, 2.35 mmol) in acetic acid (12 mL) at room temperature was added N-chlorosuccinimide (345 mg, 2.58 mmol). The mixture was warmed to 80° C. for 2 h before it was cooled to ambient temperature and concentrated. The crude mixture was purified by column chromatography (0-20% EtOAc/hexanes) to provide 5,6-dichloro-3-nitro-N-(2,2,2-trifluoroethyl)pyridin-2-amine (475 mg, 70%). MS (ES, Neg) m/z 288.0 (M−1).

The following intermediates were prepared with an analogous procedure:

-   5,6-dichloro-N-cyclobutyl-3-nitropyridin-2-amine -   5-chloro-N-cyclobutyl-3-nitro-6-(trifluoromethyl)pyridin-2-amine

Method 6. 3-Nitro-N-(2,2,2-trifluoroethyl)-6-vinylpyridin-2-amine for Use in Method 1, Step B for Preparation of 3-(2,2,2-trifluoroethyl)-5-vinyl-3H-imidazo[4,5-b]pyridin-2-amine

To a degassed mixture of 6-chloro-3-nitro-N-(2,2,2-trifluoroethyl)pyridin-2-amine (prepared by procedure described in Method 1, Step A; 400 mg, 1.8 mmol), potassium vinyltrifluoroborate (353 mg, 2.6 mmol), and cesium carbonate (1.7 g, 5.3 mmol) in a 5:1 mixture of THF/water (9 mL) was added tetrakis(triphenyphosphine) palladium (0) (200 mg, 0.18 mmol). The mixture was stirred at 80° C. for 12 h in a sealed tube, then cooled to ambient temperature and partitioned between saturated aqueous sodium bicarbonate solution (10 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (3×10 mL), and the combined organic layers were washed with brine (1×10 mL), dried over sodium sulfate, filtered, and concentrated. The crude mixture was purified by column chromatography (0-20% EtOAc/hexanes) to provide 3-nitro-N-(2,2,2-trifluoroethyl)-6-vinylpyridin-2-amine (220 mg, 51%). MS (ESI) m/z 248.4 (MH⁺).

Method 7. N-Cyclobutyl-6-morpholino-3-nitropyridin-2-amine for Use in Method 1, Step B for Preparation of 3-cyclobutyl-5-morpholino-3H-imidazo[4,5-b]pyridin-2-amine

A solution of 6-chloro-N-cyclobutyl-3-nitropyridin-2-amine (prepared by procedure described in Method 1, Step A; 530 mg, 2.3 mmol) and morpholine (0.60 mL, 6.9 mmol) in 1,4-dioxane (10 mL) was heated at 90° C. for 2 h. The reaction was cooled to room temperature, concentrated in vacuo and the residue used directly in the next step.

Method 8. N-Cyclobutyl-5-nitro-[2,3′-bipyridin]-6-amine for Use in Method 1, Step B for Preparation of 3-cyclobutyl-5-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-2-amine

A suspension of 6-chloro-N-cyclobutyl-3-nitropyridin-2-amine (prepared by procedure described in Method 1, Step A; 560 mg, 2.45 mmol), pyridin-3-ylboronic acid (360 mg, 2.9 mmol), Pd(dppf)Cl₂ (204 mg, 0.25 mmol), and cesium carbonate (2.4 g, 7.4 mmol) in DMF (10 mL) and water (5 mL) was heated at 85° C. for 2 h. The reaction was cooled to room temperature and partitioned between water and dichloromethane. The aqueous layer was extracted with CH₂Cl₂. The combined organic layers were dried over sodium sulfate, concentrated in vacuo, and purified by chromatography to provide 0.49 g, (74%) of title compound.

Method 9. N-Cyclobutyl-6-ethynyl-3-nitropyridin-2-amine for Use in Method 1, Step B for Preparation of 3-cyclobutyl-5-ethynyl-3H-imidazo[4,5-b]pyridin-2-amine

Step A

A mixture of 6-chloro-N-cyclobutyl-3-nitropyridin-2-amine (prepared by procedure described in Method 1, Step A; 250 mg, 1.10 mmol), trimethylsilylacetylene (140 mg, 1.42 mmol), Pd(PPh₃)₂Cl₂ (39 mg, 0.055 mmol), CuI (11 mg, 0.055 mmol), and triethylamine (460 μL, 3.30 mmol) in toluene (10 mL) was stirred under N₂ (g) at room temperature for 5 h. The mixture was diluted with EtOAc and washed with saturated aqueous ammonium chloride. The organic layer was dried over sodium sulfate and concentrated. Column chromatography (0-50% EtOAc/hexanes) provided 295 mg (90% yield) of N-cyclobutyl-3-nitro-6-((trimethylsilyl)ethynyl)pyridin-2-amine.

Step B

A mixture of N-cyclobutyl-3-nitro-6-((trimethylsilyl)ethynyl)pyridin-2-amine (280 mg, 0.967 mmol) and potassium carbonate (401 mg, 2.90 mmol) in dichloromethane (5 mL) and methanol (2.5 mL) was heated to 50° C. and stirred overnight. Volatiles were removed in-vacuo. Then the residue was taken up in dichloromethane and solids were removed by filtration. The filtrate was concentrated and the residue was purified by column chromatography (0-50% EtOAc/hexanes) to provide 130 mg (63% yield) of N-cyclobutyl-6-ethynyl-3-nitropyridin-2-amine. MS (ESI) m/z 218 (MH⁺).

Method 10. N,N-Bis-tert-butyl-(6-(cyclobutylamino)-5-nitropyridin-2-yl)carbamate

A solution of 6-chloro-N-cyclobutyl-3-nitropyridin-2-amine (540 mg, 2.4 mmol) and concentrated aqueous ammonia (prepared by procedure described in Method 1, Step A; 830 mg, 24 mmol) in EtOH (10 mL) was heated at 50° C. for 3 days in a sealed tube. The reaction was cooled to room temperature and concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic solution was dried over sodium sulfate and concentrated in vacuo.

The resultant residue was taken up in dichloromethane (˜10 mL) and treated with di-tert-butyl dicarbonate (570 mg, 2.6 mmol) and DMAP (15 mg, 0.12 mmol). The reaction was stirred at room temperature overnight and then purified by flash column chromatography (0-100% EtOAc/hexanes) to afford the title compound (0.96 g, 98% for 2 steps).

Method 11. N-Cyclobutyl-6-(ethylthio)-3-nitropyridin-2-amine for Use in Method 1, Step B for Preparation of 3-cyclobutyl-5-(ethylthio)-3H-imidazo[4,5-b]pyridin-2-amine

To a solution of 6-chloro-N-cyclobutyl-3-nitropyridin-2-amine (prepared by procedure described in Method 1, Step A; 800 mg, 3.52 mmol, 1 eq) in DMF (5 mL) was added ethanethiol (0.4 mL, 5.20 mmol, 1.5 eq) via syringe. Solid potassium carbonate (1.5 g, 10.5 ml, 3 eq) was added in one portion. The flask was capped and allowed to stir overnight at room temperature. The mixture was diluted with hexanes and EtOAc (approx 1:1, 75 mL) and washed with sodium bicarbonate (2 times, saturated) and brine. It was dried over sodium sulfate, filtered and concentrated to give a crude oil. This material was purified by column chromatography (5-20% EtOAc/hexanes) to give the desired product as a solid (700 mg, 78% yield). Rf=0.75 in 20% EtOAc in hexanes. MS (ESI) m/z 254 (MH⁺).

Method 12. N²-Cyclobutyl-6-fluoropyridine-2,3-diamine for Use in Method 1, Step C for Preparation of 3-cyclobutyl-5-fluoro-3H-imidazo[4,5-b]pyridin-2-amine

To a solution of N-cyclobutyl-6-fluoro-3-nitropyridin-2-amine (prepared from 2,6-difluoro-3-nitropyridine: Shackelford et al. J. Org. Chem. 2003, 68, 267, then with Method 1, step A; 350 mg, 1.65 mmol, 1 eq) in MeOH/chloroform (9:1, 10 mL) was added Pd/C (10%, 100 mg) in one portion. After a few minutes, triethylsilane (2 mL, 16.5 mmol, 10 eq) was added dropwise via syringe to produce heat and gas. The reaction was allowed to stir for 30 minutes and then passed though a plug of Celite and concentrated. The crude residue was chromatographed (10-50% EtOAc/hexanes) to give the desired product (45 mg, 15% yield).

Method 13. N-(3-Methylisoxazol-5-yl)-6-(trifluoromethyl)pyridine-2,3-diamine for use in Method 1, Step C for preparation of 3-(3-methylisoxazol-5-yl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-amine

Step A. 3-Methyl-N-(3-nitro-6-(trifluoromethyl)pyridin-2-yl)isoxazol-5-amine

Palladium(II) acetate (0.099 g, 0.441 mmol) was added to xantphos (0.511 g, 0.883 mmol) in degassed dioxane (25 mL) and the suspension was stirred for 15 min under N₂. The resulting solution was added to a mixture of 2-chloro-3-nitro-6-(trifluoromethyl)pyridine (1.00 g, 4.41 mmol), 3-methylisoxazol-5-amine (0.520 g, 5.30 mmol) and K₂CO₃ (0.915 g, 6.62 mmol) in degassed dioxane (60 mL) and the reaction mixture was refluxed overnight. Conversion was confirmed by TLC (Rf P=0.4; 30% EtOAc/Hexanes) and the solution was filtered through a plug of celite. The volatiles were removed and the crude residue was purified via column chromatography (0-100% EtOAc/hexanes) to give 0.750 g (59%) of the title compound. MS (ESI) m/z 289 (MH⁺).

Step B. N-(3-Methylisoxazol-5-yl)-6-(trifluoromethyl)pyridine-2,3-diamine

Sodium bicarbonate (0.437 g, 5.20 mmol), then sodium hydrosulfite (1.36 g, 7.81 mmol) were added to a solution of 3-methyl-N-(3-nitro-6-(trifluoromethyl)pyridin-2-yl)isoxazol-5-amine (0.750 g, 2.60 mmol) in THF/H₂O (2:1; 26 mL). The resulting reaction mixture was allowed to stir for 4 h before confirming reaction completion (TLC; Rf p=0.4 10% MeOH/DCM), diluting with H₂O and extracting (EtOAc, 2×). The combined organics were dried (MgSO₄) and the volatiles were removed to leave a crude residue that was purified via chromatography (0-5% MeOH/DCM) to give 311 mg (46%) of the title compound. MS (ESI) m/z 259 (MH⁺).

The following compounds were prepared by a procedure analogous to that described for 3-methyl-N-(3-nitro-6-(trifluoromethyl)pyridin-2-yl)isoxazol-5-amine, but with appropriate starting materials:

-   N-(5-Fluoropyridin-2-yl)-3-nitro-6-(trifluoromethyl)pyridin-2-amine -   N-(6-Methylpyridin-3-yl)-3-nitro-6-(trifluoromethyl)pyridin-2-amine -   N-(1-Methyl-1H-1,2,3-triazol-4-yl)-3-nitro-6-(trifluoromethyl)pyridin-2-amine -   5-Methyl-N-(6-methyl-3-nitropyridin-2-yl)-1,3,4-oxadiazol-2-amine

The following 3H-imidazo[4,5-b]pyridin-2-amines were prepared using the general procedures described in Section 1 with appropriate starting materials.

-   3-Cyclobutyl-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   3-Cyclobutyl-5-methoxy-3H-imidazo[4,5-b]pyridin-2-amine

-   3-isobutyl-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   5-chloro-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-amine

-   3-Cyclobutyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   6-chloro-3-cyclobutyl-3H-imidazo[4,5-b]pyridin-2-amine

-   5-chloro-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   5-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   3-cyclobutyl-5-methyl-3H-imidazo[4,5-b]pyridin-2-amine

-   5-chloro-3-isopropyl-3H-imidazo[4,5-b]pyridin-2-amine

-   3-allyl-5-chloro-3H-imidazo[4,5-b]pyridin-2-amine

-   5-chloro-3-propyl-3H-imidazo[4,5-b]pyridin-2-amine

-   3-cyclobutyl-7-methyl-3H-imidazo[4,5-b]pyridin-2-amine

-   5-chloro-3-cyclobutyl-7-methyl-3H-imidazo[4,5-b]pyridin-2-amine

-   2-Amino-3-cyclobutyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile

-   5-cyclopropyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   5-isopropoxy-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   5-(benzyloxy)-3-cyclobutyl-3H-imidazo[4,5-b]pyridin-2-amine

-   3-cyclobutyl-5-(pyridin-2-ylmethoxy)-3H-imidazo[4,5-b]pyridin-2-amine

-   3-cyclobutyl-5-((1-methyl-1H-pyrazol-5-yl)methoxy)-3H-imidazo[4,5-b]pyridin-2-amine

-   5,6-dichloro-3-cyclobutyl-3H-imidazo[4,5-b]pyridin-2-amine

-   5,6-dichloro-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   5-chloro-3-cyclobutyl-6-methyl-3H-imidazo[4,5-b]pyridin-2-amine

-   6-chloro-3-cyclobutyl-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   5-chloro-6-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   3-(2,2,2-trifluoroethyl)-5-vinyl-3H-imidazo[4,5-b]pyridin-2-amine

-   3-cyclobutyl-5-morpholino-3H-imidazo[4,5-b]pyridin-2-amine

-   5-chloro-3-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   3-cyclobutyl-5-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-2-amine

-   5-Chloro-3-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2-amine

-   3-Isopropyl-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   3-(tert-butyl)-5-chloro-3H-imidazo[4,5-b]pyridin-2-amine

-   5-chloro-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   5-chloro-3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   5-chloro-3-(tetrahydro-2H-pyran-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

-   3-(tetrahydro-2H-pyran-3-yl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   5-chloro-3-cyclobutyl-7-methyl-3H-imidazo[4,5-b]pyridin-2-amine

-   3-cyclobutyl-5-ethynyl-3H-imidazo[4,5-b]pyridin-2-amine

-   5-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-3H-imidazo[4,5-b]pyridin-2-amine

-   3-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   3-(6-methylpyridin-3-yl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-amine

-   5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

-   3-(3-methyl     isoxazol-5-yl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-am me

-   3-cyclobutyl-7-methoxy-3H-imidazo[4,5-b]pyridin-2-amine

-   3-(1-methyl-1H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-amine

Section 3. Alternative Procedures for the Synthesis of 3H-imidazo[4,5-b]pyridin-2-amine Intermediates Method 14. Preparation of 3-cyclobutyl-5-(4-methoxypiperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-amine Step A. Preparation of N-cyclobutyl-6-(4-methoxypiperidin-1-yl)-3-nitropyridin-2-amine

6-Chloro-N-cyclobutyl-3-nitropyridin-2-amine (prepared by procedure described in Method 1, Step A; 500 mg, 2.2 mmol) was dissolved in THF (0.5 mL) and 4-methoxypiperidine (2 equivalents) was added at ambient temperature. The reaction was stirred at ambient temperature overnight and concentrated. Recrystallization from EtOH afforded the title compound as a dark-yellow crystalline solid (0.48 g, 1.6 mmol).

Step B. Preparation of N²-cyclobutyl-6-(4-methoxypiperidin-1-yl)pyridine-2,3-diamine

N²-Cyclobutyl-6-(4-methoxypiperidin-1-yl)pyridine-2,3-diamine was prepared from N-cyclobutyl-6-(4-methoxypiperidin-1-yl)-3-nitropyridin-2-amine via an analogous procedure described in Method 1, Step B. The crude product used directly in Step C of the title compound synthesis.

Step C. Preparation of N-(3-cyclobutyl-5-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzamide

A solution of N²-cyclobutyl-6-(4-methoxypiperidin-1-yl)pyridine-2,3-diamine (405 mg, 1.47 mmol) in anhydrous THF (10 mL) was treated at ambient temperature under a nitrogen atmosphere with benzoylisothiocyanate (0.22 mL, 1.1 equivalents), followed by N,N′-dicyclohexylcarbodiimide (910 mg, 3 equivalents). The reaction mixture was heated at 80° C. for 18 h and allowed to cool to ambient temperature. The mixture was concentrated, treated with water, and the resulting material extracted with dichloromethane and EtOAc. The combined organics were dried over anhydrous sodium sulfate and concentrated. Chromatography on silica with 0-2% MeOH in dichloromethane as eluent afforded a partially purified desired product (229 mg), which was carried directly into Step D.

Step D. Preparation of 3-cyclobutyl-5-(4-methoxypiperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-amine

A solution of N-(3-cyclobutyl-5-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzamide (200 mg) in MeOH (5 mL) was treated with hydrazine (0.2 mL) at ambient temperature under nitrogen. The reaction vessel was sealed and heated at 100° C. until the reaction was judged complete by LC/MS analysis. The reaction mixture was cooled, concentrated, and the residue chromatographed on silica (0-10% MeOH/DCM) to afford the title compound (125 mg). MS (ESI) m/z 302 (MH⁺).

Method 15. Synthesis of 3-cyclobutyl-3H-imidazo[4,5-b]pyridin-2-amine

A mixture of 5-chloro-3-cyclobutyl-3H-imidazo[4,5-b]pyridin-2-amine (800 mg, 3.59 mmol), ammonium formate (4.5 g, 72 mmol), and 10% palladium on carbon (100 mg) in EtOH (70 mL) was heated to 50° C. for 18 h. The mixture was filtered through Celite© and concentrated. Column chromatography (0-10% MeOH/DCM) provided 742 mg of title compound with formic acid (as indicated by ¹H NMR). The solid was dissolved in EtOAc and washed with aqueous saturated NaHCO₃. The organic layer was dried over sodium sulfate and concentrated to provide 0.66 g (98%) of title compound. MS (ESI) m/z 189.2 (MH⁺).

The following compound was prepared according to the method described in Method 15, but with 5-chloro-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-amine as the starting material: 3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-amine.

Section 6. Preparation of Acids Method 16. Preparation of 2-(2,2-dimethylcyclopropyl)acetic acid

Step A

To a solution of diiodomethane (0.19 mL, 2.4 mmol) in dichloromethane (6 mL) at 0° C. was added diethylzinc solution (1M in hexane, 2.4 mL, 2.4 mmol). After 10 min, 4-methyl-3-penten-1-ol (0.20 mL, 1.2 mmol) was added. The mixture was allowed to warm to room temperature over 2.5 h. The mixture was quenched with water, then partitioned between EtOAc and aqueous 1 N hydrochloric acid. The aqueous portion was extracted with dichloromethane 2 times. The combined organic extracts were dried over sodium sulfate and concentrated to give 137 mg of 2-(2,2-dimethylcyclopropyl)ethanol, which was used in the next step without further purification.

Step B

To a solution of 2-(2,2-dimethylcyclopropyl)ethanol (135 mg, 1.20 mmol) in acetone (15 mL) was added Jones reagent (1.8 mL). After 2 h, the mixture was quenched with 1 mL of isopropanol, then partitioned between ether and water. The aqueous layer was extracted again with ether. The organic layer was dried over sodium sulfate and concentrated to provide 100 mg (65% yield) of 2-(2,2-dimethylcyclopropyl)acetic acid. ¹H NMR (CDCl₃): δ 2.37 (dd, J=7.6, 3.2 Hz, 2H), 1.08 (s, 3H), 1.06 (s, 3H), 0.91-0.83 (m, 1H), 0.54 (dd, J=8.6, 4.6 Hz, 1H), 0.054 (t, J=4.8 Hz, 1H).

Method 17. Procedure for Synthesis of [3.2.0]-oxabicyclic acetic acids

Step A. Synthesis of (Z) and (E)-methyl 2-((1S,5R)-5-methyl-2-oxabicyclo[3.2.0]heptan-7-ylidene)acetate

To a suspension of sodium hydride (80 mg, 60% dispersion, 2.0 mmol) in THF (4 mL) at 0° C. under nitrogen, was added trimethylphosphonoacetate (360 mg, 2.0 mmol). The reaction was stirred at 0° C. for 20 min and then (1S,5S)-5-methyl-2-oxabicyclo[3.2.0]heptan-7-one (Snider, B. B. et al. J. Am. Chem. Soc. 1985, 107, 2194; 230 mg, 1.8 mmol) in THF (4 mL) was added. The reaction was warmed to room temperature overnight (20 h) and quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with EtOAc. LC-MS analysis of the crude extracts showed 2 peaks (2:1 ratio by UV), both with m/z=183 (M+H for desired products). The combined organic extracts were dried over sodium sulfate, concentrated in vacuo, and purified by flash column chromatography (0-60% EtOAc/hexanes) to afford the (Z) (130 mg) and (E) (100 mg) isomers as clear colorless oils (combined yield of 69%). Isomer assignments were based on NOESY experiments.

(E) isomer: ¹H NMR (CDCl₃): δ 5.92 (td, J=3.8, 1.2 Hz, 1H), 4.47 (t, J=1.2 Hz, 1H), 4.14-4.10 (m, 1H), 3.90-3.85 (m, 1H), 3.71 (s, 3H), 2.87-2.78 (m, 2H), 1.87 (ddd, J=4.8, 1.7, 0.6 Hz, 1H), 1.69 (d, J=7.9 Hz, 1H), 1.54 (s, 1H), 1.37 (s, 3H).

(Z) isomer: ¹H NMR (CDCl₃): δ 5.78 (q, J=2.3H, 1H), 4.82 (q, J=1.7 Hz, 1H), 4.17 (td, J=7.8, 1.3 Hz, 1H), 3.90-3.85 (m, 1H), 3.73 (s, 3H), 2.58-2.52 (m, 2H), 1.87 (ddd, J=12.2, 5.4, 0.8 Hz, 1H), 1.75-1.69 (m, 1H), 1.35 (s, 3H).

Step B. Synthesis of methyl 2-((1R,5R)-5-methyl-2-oxabicyclo[3.2.0]heptan-7-yl)acetates

A solution of (E)-methyl 2-((1 S,5R)-5-methyl-2-oxabicyclo[3.2.0]heptan-7-ylidene)acetate (70 mg, 0.38 mmol) in EtOH (5 mL) was purged with nitrogen for 15 min and then palladium on carbon (50 mg, 10% Pd/C, 50% water) was added. The mixture was purged with nitrogen for an additional 2 min and then the reaction was capped with a hydrogen balloon and stirred for 4 h at room temperature. Analysis by LC-MS showed no UV peaks and 2 peaks in the TIC (˜1:1 ratio) with m/z=185. The reaction was purged with nitrogen for 15 min and filtered through Celite. The filtrate was concentrated in vacuo and purified by flash column chromatography (0-60% EtOAc/hexanes) to afford a single isomeric product (stereochemistry was not assigned; designated as diastereomer A; 46 mg, 66%) as a clear, colorless oil.

(Z)-methyl 2-((1 S,5R)-5-methyl-2-oxabicyclo[3.2.0]heptan-7-ylidene)acetate (110 mg, 0.55 mmol) was subjected to similar conditions to afford diastereomer A (35 mg, 32%) and diastereomer B (70 mg, 64%) as clear, colorless oils. NMR data:

Diastereomer A: ¹H NMR (CDCl₃): δ 4.15 (TD, J=9.1, 1.5 Hz, 1H), 4.07 (dd, J=5.6, 3.9 Hz, 1H), 3.95-3.90 (m, 1H), 3.65 (s, 3H), 2.78-2.74 (m, 1H), 2.48 (dd, J=16.2, 8.0 Hz, 1H), 2.30 (dd, J=17.2, 7.8 Hz, 1H), 1.98 (td, J=9.5, 2.9 Hz, 1H), 1.68 (ddd, J=12.0, 6.6, 1.4 Hz, 1H), 1.61-1.59 (m, 1H), 1.49 (dd, J=12.1, 9.1 Hz, 1H), 1.33 (s, 3H).

Diastereomer B: ¹H NMR (CDCl₃): δ 4.14-4.08 (m, 1H), 4.01-3.96 (m, 1H), 3.82 (dd, J=1.9, 1.0 Hz, 1H), 3.67 (s, 3H), 2.56 (dd, J=15.3, 6.9 Hz, 1H), 2.44 (dd, J=15.2, 9.0 Hz, 1H), 2.38-2.34 (m, 1H), 1.99 (dd, J=12.5, 9.5 Hz, 1H), 1.76 (ddd, J=12.2, 5.8, 2.3 Hz, 1H), 1.62-1.56 (m, 1H), 1.43 (dd, J=12.6, 6.4 Hz, 1H), 1.39 (s, 3H).

Step C. Synthesis of 2-((1R,5R)-5-methyl-2-oxabicyclo[3.2.0]heptan-7-yl)acetic acids

To a solution of methyl 2-((1R,5R)-5-methyl-2-oxabicyclo[3.2.0]heptan-7-yl)acetate (diastereomer A, 89 mg, 0.48 mmol) in THF (2.5 mL) and water (0.8 mL) was added LiOH.H₂O (31 mg, 0.73 mmol). The reaction was stirred at room temperature for 23 h and then quenched with dilute aqueous HCl. Brine (10 mL) was added and the mixture was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the titled compound (41 mg, 50%) as a clear, colorless film. ¹H NMR (CDCl₃): δ 4.19 (td, J=7.6, 1.6 Hz, 1H), 4.12 (dd, J=5.7, 2.9 Hz, 1H), 3.98-3.93 (m, 1H), 2.78-2.73 (m, 1H), 2.51 (dd, J=16.1, 8.7 Hz, 1H), 2.35 (dd, J=16.1, 7.3 Hz, 1H), 2.00 (ddd, J=9.6, 2.9, 2.6 Hz, 1H), 1.71 (ddd, J=12.1, 5.7, 1.5 Hz, 1H), 1.64-1.58 (m, 1H), 1.51 (dd, J=12.2, 9.0 Hz, 1H), 1.33 (s, 3H) [note: CC₂H was not observed].

Subjection of diastereomer B (80 mg, 0.43 mmol) to similar conditions afforded the corresponding acid (29 mg, 40%). ¹H NMR (CDCl₃): δ 4.11 (tdd, J=9.1, 2.4, 1.6 Hz, 1H), 4.03-3.98 (m, 1H), 3.85 (d, J=2.0 Hz, 1H), 2.59 (dd, J=15.6, 7.4 Hz, 1H), 2.47 (dd, J=15.6, 8.6 Hz, 1H), 3.99-3.60 (m, 1H), 2.02 (dd, J=12.6, 9.5 Hz, 1H), 1.78 (ddd, J=13.2, 5.8, 2.4 Hz, 1H), 1.63-1.57 (m, 1H), 1.44 (dd, J=12.6, 6.5 Hz, 1H), 1.30 (s, 3H) [note: CC₂H was not observed].

Method 18. Procedure for Synthesis of [2.2.1]oxabicyclic acetic acids

Step A. Synthesis of (Z) and (E)-methyl 2-((1R,4R)-7-oxabicyclo[2.2.1]hept-5-en-2-ylidene)acetates

To a suspension of sodium hydride (840 mg, 60% dispersion, 21 mmol) in THF (73 mL) at 0° C. under nitrogen, was added trimethylphosphonoacetate (3.6 g, 20.0 mmol). The reaction was stirred for 20 min at 0° C. and then (1R,4R)-7-oxabicyclo[2.2.1]hept-5-en-2-one (Black, K. A. et al. Helv. Chim. Acta, 1984, 1614; Warm, A . . . Helv. Chim. Acta, 1987, 70, 695; 2.0 g, 18.2 mmol) in THF (18 mL) was added over 10 min. The reaction was warmed slowly to room temperature and then stirred for 2 days. The reaction was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash column chromatography (0-70% EtOAc/hexanes) to afford the titled compounds (1.67 g, 55%) as a 1.0:0.6 mixture (by ¹H NMR) of alkene isomers (alkene geometry was not assigned).

Step B. Synthesis of methyl 2-((1R,2R,4S)-7-oxabicyclo[2.2.1]heptan-2-yl)acetate and methyl 2-((1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-yl)acetate

A solution of (Z) and (E)-methyl 2-((1R,4R)-7-oxabicyclo[2.2.1]hept-5-en-2-ylidene)acetates (1.67 g, 10.1 mmol) in EtOAc (100 mL) was purged with nitrogen for 20 min. Palladium on carbon (300 mg, 10% Pd/C, 50% water) was added and the reaction was purged with nitrogen for 2 min before being capped with a hydrogen balloon and stirred at room temperature for 4 h. The reaction was purged with nitrogen for 20 min and then filtered through Celite. The filtrate was concentrated in vacuo and purified by flash column chromatography (0-70% EtOAc/hexanes) to afford diastereomer A (0.50 g, 29%), diastereomer B (0.38 g, 22%), and mixed fractions (780 mg, 45%, 1:3 mixture of diastereomer A to B). Assignment of the relative stereochemistry was done based on NOESY experiments and ChemDraw3D modeling.

Diastereomer A: ¹H NMR (CDCl₃): δ 4.55 (t, J=5.5 Hz, 1H), 4.27 (d, J=4.8 Hz, 1H), 3.67 (s, 3H), 2.44 (quint, J=7.7 Hz, 1H), 2.25 (d, J=6.9 Hz, 1H), 2.21-2.11 (m, 1H), 1.76-1.62 (m, 3H), 1.53-1.38 (m, 2H), 1.33-1.30 (m, 1H).

Diastereomer B: ¹H NMR (CDCl₃): δ 4.55 (dd, J=5.0, 4.9 Hz, 1H), 4.27 (d, J=4.8 Hz, 1H), 3.67 (s, 3H), 2.43 (q, J=7.7 Hz, 1H), 2.24 (d, J=6.9 Hz, 1H), 2.21-2.11 (m, 1H), 1.76-1.62 (m, 3H), 1.53-1.38 (m, 2H), 1.33-1.31 (m, 1H).

Step C. Synthesis of 2-((1R,2R,4S)-7-oxabicyclo[2.2.1]heptan-2-yl)acetic acid

To a solution of methyl 2-((1R,1R,4S)-7-oxabicyclo[2.2.1]heptan-2-yl)acetate (Diastereomer A, 500 mg, 2.9 mmol) in THF (15 mL) and water (5 mL) was added LiOH.H₂O (180 mg, 4.4 mmol). The reaction was stirred at rt for 8 h and then quenched with dilute aqueous HCl. The mixture was extracted with EtOAc and the combined extracts were dried with sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (440 mg, 96%) as a thick, yellow oil. ¹H NMR (CDCl₃): δ 4.57 (dd, J=5.0, 4.8 Hz, 1H), 4.31 (d, J=4.8 Hz, 1H), 2.47 (dd, J=16.2, 8.1 Hz, 1H), 2.27 (dd, J=16.2, 6.8 Hz, 1H), 2.21-2.10 (m, 2H), 1.78-1.63 (m, 2H), 1.53-1.39 (m, 2H), 1.36-1.22 (m, 2H)

Synthesis of 2-((1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-yl)acetic acid

To a solution of methyl 2-((1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-yl)acetate (Diastereomer B, 380 mg, 2.2 mmol) in THF (11 mL) and water (4 mL) was added LiOH.H₂O (140 mg, 3.3 mmol). The reaction was stirred at room temperature for 8 h and then quenched with dilute aqueous HCl. The mixture was extracted with EtOAc and the combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (320 mg, 91%) as a clear, colorless oil. ¹H NMR (CDCl₃): δ 4.57-4.53 (m, 2H), 2.53-2.39 (m, 3H), 2.13-2.04 (m, 1H), 1.79-1.62 (m, 3H), 1.44-1.37 (m, 1H), 1.01-0.96 (m, 1H) [note: CC₂H not observed].

Method 19. General procedure for synthesis of 3-tert-butoxyproprionoic acids

Step A. Synthesis of 3-(tert-butoxy)-2,2-dimethylpropanoic acid

Isobutylene (approx. 8.7 g) was bubbled into a solution of methyl 3-hydroxy-2,2-dimethylpropanoate (1.0 g, 7.6 mmol) in dichloromethane (30 mL) at 0° C. Sulfuric acid (3 drops, 18 M) was added and the reaction vessel was sealed. The reaction was warmed to room temperature overnight then diluted with dichloromethane and washed successively with saturated aqueous sodium bicarbonate and brine. The resultant organic solution was dried with sodium sulfate and concentrated in vacuo to give an oil (1.29 g) which was used directly in the next step.

Step B

To a solution of the above ester (1.29 g, 6.86 mmol) in MeOH/THF/water (14/5/6 mL) was added potassium hydroxide (1.54 g, 27.4 mmol).

The reaction was stirred at room temperature for 1 h then heated to 75° C. for 1 h. After cooling to room temperature, brine (50 mL) was added and the pH was adjusted to 4 with 2N aqueous HCl. The mixture was extracted with EtOAc and the combined organic layers were dried with sodium sulfate, concentrated in vacuo, and purified by flash column chromatography (0-20% MeOH/DCM) to afford the title compound (690 mg, 58%) as a pale orange solid.

The following additional intermediates were prepared from an appropriate starting material using Method 19:

-   (R)-3-(tert-butoxy)-2-methylpropanoic acid -   (S)-3-(tert-butoxy)-2-methylpropanoic acid

Method 20. General procedure for synthesis of 3-alkoxypropanoic acids

Step A. Preparation of tert-butyl 3-(cyclohexylmethoxy)acrylate

To a solution of cyclohexylmethanol (0.98 g, 8.7 mmol) and DABCO (88 mg, 0.79 mmol) in THF at room temperature under nitrogen was added tert-butyl propiolate (1.0 g, 7.9 mmol). The reaction was stirred for 2 days and then concentrated in vacuo and purified by flash column chromatography (EtOac/hexanes 0-10%) to afford the titled compound (1.4 g, 75%) as a colorless oil. [note: products were generally a mixture of E and Z alkene isomers]

Step B. Preparation of tert-butyl 3-(cyclohexylmethoxy)propanoate

A solution of tert-butyl 3-(cyclohexylmethoxy)acrylate (1.4 g, 5.8 mmol) in EtOAc (50 mL) was purged with nitrogen and then palladium on carbon (300 mg, 10% Pd/C, 50% water) was added. The reaction was stirred under a hydrogen atmosphere for 1 h and then filtered through Celite and concentrated in vacuo to afford the title compound (1.18 g, 84%). ¹H NMR (CDCl₃): δ 3.68 (t, J=6.6 Hz, 2H), 2.47 (t, J=6.5 Hz, 2H), 1.90-1.88 (m, 2H), 1.73-1.71 (m, 2H), 1.45 (s, 9H), 1.28-1.19 (m, 6H).

Step C. Preparation of 3-(cyclohexylmethoxy)propanoic acid

Hydrochloric acid (12 mL, 4N in 1,4-dioxane, 48 mmol) was added to tert-butyl 3-(cyclohexylmethoxy)propanoate (1.18 g, 4.9 mmol) at 0° C. The reaction was kept at 0° C. for 5 min and then stirred at room temperature overnight. The reaction was concentrated in vacuo and co-evaporated with dichloromethane to afford the title compound (800 mg, 89%). ¹H NMR (CDCl₃): δ 3.75 (t, J=6.2 Hz, 2H), 2.63 (d, J=6.2 Hz, 2H), 1.92-1.89 (m, 2H), 1.74-1.71 (m, 2H), 1.33-1.21 (m, 6H).

The following additional intermediates were prepared from an appropriate starting material using Method 20:

-   3-(cyclopentyloxy)propanoic acid -   3-isopropoxypropanoic acid -   3-cyclobutoxypropanoic acid -   3-(cyclohexyloxy)propanoic acid -   3-((4,4-difluorocyclohexyl)oxy)propanoic acid -   3-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yloxy)propanoic acid -   3-((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yloxy)propanoic acid -   3-((1R,4S)-7-oxabicyclo[2.2.1]heptan-2-yloxy)propanoic acid

Method 21. Preparation of 2-(4,4-difluoropiperidin-1-yl)acetic acid

Step A. Preparation of 2-(4,4-difluoropiperidin-1-yl)acetic acid ethyl ester

Prepared from 4,4-difluoropiperidine hydrochloride and ethyl bromoacetate via procedure from WO200911450, p. 76-77.

Step B. Preparation of 2-(4,4-difluoropiperidin-1-yl)acetic acid

2-(4,4-Difluoropiperidin-1-yl)acetic acid ethyl ester (0.61 mmol) was treated at ambient temperature with 1 N aqueous lithium hydroxide (2 equivalents). The reaction was stirred at ambient temperature for 3 h. The mixture was acidified to pH ˜1 with concentrated hydrochloric acid and concentrated to afford a white solid. The crude product, as the hydrochloride salt, was used directly in the amide bond forming reaction. The following amino acids were prepared in a method analogous to the one for 2-(4,4-difluoropiperidin-1-yl)acetic acid from ethyl bromoacetate and the appropriate amine hydrochlorides:

-   2-(3,3-difluoropiperidin-1-yl)acetic acid -   2-(3,3-difluoropyrrolidin-1-yl)acetic acid

Method 22. Preparation of 3-(1-(trifluoromethyl)cyclopropyl)propanoic acid Step A. Preparation of 5-(hydroxy(1-(trifluoromethyl)cyclopropyl)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

The title compound was prepared from Meldrum's acid and 1-(trifluoromethyl)cyclopropanecarboxylic acid via general procedure outlined in J. Comb. Chem. 2002, 4, 470-474.

Step B. Preparation of 2,2-dimethyl-5-((1-(trifluoromethyl)cyclopropyl)methyl)-1,3-dioxane-4,6-dione

To a cooled (−5° C.) solution of the product from Step A (5 mmol) in dichloromethane (10 mL) was added glacial acetic acid (3.2 mL) and the mixture treated with sodium borohydride (483 mg, added as a solid, in small portions, over 15 min. The reaction was allowed to warm to ambient temperature and stirring continued until the reaction was judged complete by TLC. The mixture was concentrated, diluted with water and extracted with dichloromethane and EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated. Chromatography on silica with ethyl acetate as eluent afforded 0.44 g of the title compound.

Step C. Preparation of 3-(1-(trifluoromethyl)cyclopropyl)propanoic acid

The product from Step B (0.39 g) was refluxed in EtOH (6 mL) for 6 hours. The reaction mixture was concentrated to afford an oil. The oil was dissolved in dioxane (1 mL) and treated with of 2 N aqueous lithium hydroxide (2 equivalents). Stirring was continued overnight, then the mixture was concentrated and acidified with concentrated sulfuric acid. The mixture was extracted with dichloromethane and EtOAc, the organics were dried over sodium sulfate and concentrated. The residue was suspended in a 1:1 dioxane/2 N aqueous lithium hydroxide mixture (4 mL), and heated at 100° C. for 12 h in a microwave reactor. The reaction mixture was concentrated, extracted with dichloromethane and EtOAc, the organics were dried over sodium sulfate and concentrated to afford the desired product as an oil (0.15 g).

In an analogous fashion was prepared (S)-3-(tetrahydrofuran-2-yl)propanoic acid from (S)-tetrahydrofuran-2-carboxylic acid.

Method 23. Preparation of 3-methoxy-3-methylbutanoic acid

-   Reference: Schmidt, A.-K. C.; Stark, B. W. Org Lett. 2011, 13,     4164-4167.

To a solution of 3-methoxy-3-methylbutan-1-ol (0.6 g, 5 mmol) in acetonitrile (20 mL) was added N-methyl morpholine N-oxide mono hydrate (6.8 g, 50 mmol, 10 eq) and the mixture was allowed to stir at room temperature. After 5 min, TPAP (175 mg, 0.5 mmol, 0.1 eq) was added in one portion and the reaction was allowed to stir for 3 h before the bulk of the solvent was carefully removed on a rotary evaporator (caution, the product is volatile). The residue was purified by column chromatography (50-100% EtOAc/hexanes). The hexanes and EtOAc were removed by both rotary evaporator and a short period of time to high vacuum. The product is volatile and must not be left under vacuum for more than 30 sec. The resulting purified acid was diluted with DMF (7 mL) to make an approximately 0.2 M solution that was used for amide coupling reaction as is. R_(f)=0.4 to 0.8 streak in 100% EtOAc, not UV active, stains purple to anisaldehyde. MS (ESI) m/z 131 (MH⁻). ¹H NMR (CDCl₃): δ 12.0-9.0 (bs, 1H), 3.30 (s, 3H), 2.57 (s, 2H), 1.32 (s, 6H).

Method 24. Preparation of 2-(bicyclo[4.2.0]octa-1,3,5-trien-7-yl)acetic acid

Step A

Borane in THF solution (1 M, 4 mL, 1.2 eq) was added drop-wise to a solution of bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (500 mg, 3.38 mmol) in THF (6 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over MgSO₄. Purification by chromatography (5-20% EtOAc/hexanes) provided bicyclo[4.2.0]octa-1,3,5-trien-7-ylmethanol (388 mg, 86%).

Step B

p-Toluenesulfonyl chloride (662 mg, 3.47 mmol), triethylamine (0.605 ml), and DMAP (35 mg, 0.29 mmol) were added to a solution of bicyclo[4.2.0]octa-1,3,5-trien-7-ylmethanol (388 mg, 2.89 mmol) in dichloromethane (12 mL) at room temperature and the reaction mixture was stirred overnight. Saturated aqueous NH₄Cl was added to the reaction mixture, and the mixture was extracted with dichloromethane, dried over MgSO₄ and purified by chromatography (5-20% EtOAc/hexanes) to provide bicyclo[4.2.0]octa-1,3,5-trien-7-ylmethyl 4-methylbenzenesulfonate (830 mg, 99%).

Step C

Potassium cyanide (54 mg, 0.83 mmol) was added to a solution of bicyclo[4.2.0]octa-1,3,5-trien-7-ylmethyl 4-methylbenzenesulfonate (200 mg, 0.694 mmol) in DMF (2 mL). The reaction mixture was stirred at 100° C. in a microwave reactor overnight. The reaction was then diluted with water and the mixture was extracted with EtOAc, dried over MgSO₄, and purified by chromatography (5-50% EtOAc/hexanes) to provide 2-(bicyclo[4.2.0]octa-1,3,5-trien-7-yl)acetonitrile (74 mg, 75%).

Step D

To 2-(bicyclo[4.2.0]octa-1,3,5-trien-7-yl)acetonitrile (100 mg, 0.698 mmol) was added 30% aqueous hydrochloric acid (1.25 mL). The reaction mixture was heated to reflux for 18 h. After cooling to room temperature, the reaction mixture was diluted with water, extracted with EtOAc, dried over MgSO₄ and purified by chromatography (5-50% EtOAc/hexanes) to provide 2-(bicyclo[4.2.0]octa-1,3,5-trien-7-yl)acetic acid (90 mg, 0.555 mmol, 80%).

Section 4. Reaction of 3H-imidazo[4,5-b]pyridin-2-amine Intermediates to Form Title Compounds in Table 1

Procedure A. General Procedure for Amide Formation Using Amino Acid Coupling Reaction with HATU (Table 1)

A solution of appropriate 3H-imidazo[4,5-b]pyridin-2-amine intermediate (0.22 mmol), carboxylic acid (0.27 mmol), (dimethylamino)-N,N-dimethyl-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (HATU, 0.11 g, 0.29 mmol), and N,N-diisopropylethylamine (78 μL, 0.45 mmol) in DMF or THF (2 mL) was stirred for 18 h at room temperature. The mixture was diluted with EtOAc and washed sequentially with saturated aqueous NaHCO₃ and water (4 times). The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography (0-100% EtOAc/hexanes or 0-10% MeOH/DCM) provided title compounds.

Procedure B. General Procedure for Amide Formation Using Acyl Chlorides (Table 1)

To a solution of appropriate 3H-imidazo[4,5-b]pyridin-2-amine intermediate (0.22 mmol) in THF (1 mL) was added pyridine (27 μL, 0.33 mmol) and acyl chloride (0.26 mmol). The reaction mixture was stirred for 18 h. The mixture was partitioned between EtOAc and water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography (0-100% EtOAc/hexanes) to provide title compounds.

Procedure C. General Procedure for Amide Formation Using Acyl Chlorides (Table 1)

To a mixture of appropriate 3H-imidazo[4,5-b]pyridin-2-amine intermediate (0.14 mmol) and pyridine (0.41 mmol) in dichloromethane (1 mL) was added acyl chloride (0.16 mmol). The mixture was stirred at room temperature for 2 h and then concentrated in vacuum. The residue was dissolved in methanol (1 mL). To the solution, aqueous 1 N NaOH (1 mL) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. The residue was co-evaporated with heptane in vacuum to remove pyridine and then purified by column chromatography, eluting with solvent A (100%) to solvent B (5%) gradient (where A is methylene chloride, B is methylene chloride/methanol 90:10), to provide the title compounds.

Procedure D. General Procedure for Amide Formation Using Amino Acid Coupling Reaction with EDC (Table 1)

A solution of appropriate imidazo[4,5-b]pyridin-2-amine (0.13 mmol), carboxylic acid (0.16 mmol), EDC (0.19 mmol), HOBt (0.19 mmol) and DIPEA (0.66 mmol) in THF (1 mL) was heated at 50° C. under nitrogen for 2-4 h. The reaction was cooled to room temperature, diluted with EtOAc and washed with water. The organic solution was concentrated in vacuo and purified by column chromatography (silica gel, 0-10% MeOH/DCM) to afford titled compounds.

Procedure E. General Procedure for Amide Formation Using Acylbenzotriazoles

-   Reference: Katritzky, Synlett, 2005, 11, 1656.

A solution of appropriate 3H-imidazo[4,5-b]pyridin-2-amine intermediate (0.66 mmol) and triethylamine (0.5 mL, 3.3 mmol, 5 eq) in THF (3 mL) was stirred for 5 min at room temperature. To this solution was added a solution of premade acylbenzotriazole (0.7 M in DCM, 3.0 mL, 2.0 mmol, 3 eq) and the mixture was placed in a 50° C. sand bath for 12 hours. The mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed sequentially with saturated aqueous Na₂CO₃ (3 times) and brine. The organic layer was dried over Na₂SO₄ and concentrated. Purification by column chromatography (0-100% EtOAc/hexane or 0-10% MeOH/DCM) provided title compounds.

Section 5. Exemplary Syntheses for Examples in Table 1 Example 65. Preparation of N-(3-cyclobutyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)-2-(4-fluorophenyl)acetamide Step A. Alternative Preparation of N-cyclobutyl-3-nitro-5-(trifluoromethyl)pyridin-2-amine

To a mixture of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1.00 g, 4.41 mmol) and NaHCO₃ (1.12 g, 13.2 mmol) in EtOH (10 mL) was added cyclobutylamine (0.94 g, 13.2 mmol) drop-wise over 10 minutes. The mixture was stirred for 30 min, absorbed onto silica and purified on a 40 g ISCO gold silica gel column, eluting with a hexanes (100%) to hexanes (95%)/EtOAc (5%) gradient, to provide the desired compound (1.05 g, 91%) as a bright yellow solid.

Step B. Alternative Preparation of N²-cyclobutyl-5-(trifluoromethyl)pyridine-2,3-diamine

A mixture of N-cyclobutyl-3-nitro-5-(trifluoromethyl)pyridin-2-amine (500 mg, 1.91 mmol), iron powder (535 mg, 9.57 mmol) and ammonium chloride (153 mg, 2.87 mmol) in EtOH (8 mL)/water (2 mL) was heated to 85° C. for 2 h. The mixture was absorbed onto silica and purified on a 24 g ISCO Gold silica gel column, eluting with a hexanes (100%) to hexanes (50%)/ethyl acetate (50%) gradient, to provide the desired compound (380 mg, 86%) as a green oil.

Step C. Preparation of 3-cyclobutyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-amine

N²-Cyclobutyl-5-(trifluoromethyl)pyridine-2,3-diamine (380 mg, 1.64 mmol) and cyanogen bromide (3 N in CH₂Cl₂, 0.66 mL, 1.97 mmol) were stirred in EtOH (3 mL) for 24 h. The mixture was concentrated and partitioned between EtOAc and NaHCO₃ solution and the organic layer absorbed onto silica and purified on 24 g ISCO Gold silica gel column, eluting with a hexanes (100%) to ethyl acetate (100%) gradient, to provide the desired compound (90 mg, 21%) as a white solid.

Step D. Preparation of N-(3-cyclobutyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)-2-(4-fluorophenyl)acetamide

To a mixture of 3-cyclobutyl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-amine (100 mg, 0.39 mmol) and diisopropylethylamine (140 μL, 0.78 mmol) in dichloromethane (5 mL) was added 2-(4-fluorophenyl)acetyl chloride (70 μL, 0.50 mmol). The mixture was stirred for 24 h, washed with NaHCO₃ solution and the organic layer absorbed onto silica and purified on a 12 g ISCO Gold silica gel column, eluting with solvent A (100%) to solvent B (5%) gradient (where A is methylene chloride, B is methylene chloride/methanol/concentrated ammonium hydroxide 80:18:2), to provide the desired compound (82 mg, 53%) as a white solid. MS (ESI) m/z 393 (MH⁺).

Example 162. Preparation of N-(5-ethyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-yl)-3,3-dimethylbutanamide

A solution of 3,3-dimethyl-N-(3-(2,2,2-trifluoroethyl)-5-vinyl-3H-imidazo[4,5-b]pyridin-2-yl)butanamide (20 mg, 0.06 mmol) in methanol (1.2 mL) was passed through an H-cube at 10 bar and 25° C. The resulting solution was concentrated to provide N-(5-ethyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-yl)-3,3-dimethylbutanamide (15 mg, 75%) MS (ESI) m/z 343.2 (MH⁺).

Example 217. Preparation of N-(5-(hydroxymethyl)-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-yl)-3,3-dimethylbutanamide

Step A

A mixture of 3,3-dimethyl-N-(3-(2,2,2-trifluoroethyl)-5-vinyl-3H-imidazo[4,5-b]pyridin-2-yl)butanamide (30 mg, 0.14 mmol), 2.5% osmium tetroxide solution (10 μL, 0.007 mmol), and NMO (32 mg, 0.27 mmol) were stirred at room temperature in dichloromethane (1.4 mL) for 4 h. The crude mixture was purified by column chromatography (0-10% MeOH/DCM) to provide N-(5-(1,2-dihydroxyethyl)-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-yl)-3,3-dimethylbutanamide (27 mg, 54%).

Step B

A mixture of N-(5-(1,2-dihydroxyethyl)-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-yl)-3,3-dimethylbutanamide (20 mg, 0.05 mmol) and sodium periodate (17 mg, 0.08 mmol) were stirred in a biphasic 5:1 dichloromethane/water mixture (0.5 mL) at room temperature for 8 h. The mixture was then partitioned between water (3 mL) and dichloromethane (5 mL) and the aqueous was extracted with dichloromethane (1×5 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to provide crude N-(5-formyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-yl)-3,3-dimethylbutanamide which was used directly in the following step.

Step C

To a solution of crude N-(5-formyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-yl)-3,3-dimethylbutanamide from Step B in MeOH (0.5 mL) was added sodium borohydride (6 mg, 0.2 mmol) at room temperature. The mixture was stirred for 20 min before partitioning between water (5 mL) and EtOAc (10 mL). The aqueous was extracted with EtOAc (3×10 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude mixture was purified by column chromatography (50-100% EtOAc/hexanes) to provide N-(5-(hydroxymethyl)-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-2-yl)-3,3-dimethylbutanamide (10 mg, 55%, 2 steps). MS (ESI) m/z 345.2 (MH⁺).

Example 176. Preparation of isobutyl (5-chloro-3-cyclobutyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

To a solution of 5-chloro-3-cyclobutyl-3H-imidazo[4,5-b]pyridin-2-amine (50 mg, 0.22 mmol) and isobutylchloroformate (44 μL, 0.34 mmol) in dichloromethane (2.2 mL) at room temperature was added N,N-diisopropylethylamine (117 μL, 0.67 mmol). The mixture was stirred at room temperature for 10 min before it was concentrated. The crude mixture was purified by column chromatography (10-100% EtOAc/hexanes) to provide isobutyl (5-chloro-3-cyclobutyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (22 mg, 30%). MS (ESI) m/z 323.2 (MH⁺).

Example 259. Preparation of isobutyl N-(3-cyclobutyl-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)-4-hydroxy-3,3-dimethylbutanamide

To a solution of 3-cyclobutyl-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-amine (18 mg, 0.070 mmol), and 4,4-dimethyldihydrofuran-2(3H)-one (16 mg, 0.14 mmol) in THF (1.5 mL) was added trimethylaluminum (2 M in hexane, 0.21 mL, 0.42 mmol). The mixture was heated to 70° C. After 3 h, the mixture was cooled to room temperature, then quenched slowly with 1M Rochelle's salt. After bubbling ceased, the mixture was poured into saturated aqueous NaHCO₃ and extracted with EtOAc. The organic layer was washed with water 3 times, then dried over sodium sulfate and concentrated. Column chromatography (0-10% MeOH/DCM provided 9.3 mg (36% yield) of N-(3-cyclobutyl-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)-4-hydroxy-3,3-dimethylbutanamide.

Example 212. Preparation of 3,3-dimethyl-N-(3-(3-methylisoxazol-5-yl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)butanamide

3,3-Dimethylbutanoyl chloride (0.623 mL, 3.47 mmol) was added dropwise to a 0° C. solution of 3-(3-methyl isoxazol-5-yl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-amine (0.100 g, 0.347 mmol) and triethylamine (0.599 mL, 5.20 mmol) in CH₂Cl₂ (7 mL) and the reaction mixture was allowed to warm to ambient temperature and stir for 30 min. A solution of NH₃ (2.0 M in MeOH, 7 mL) was added and the mixture was stirred at 50° C. for 2 h before quenching with saturated aqueous NH₄Cl. The aqueous portion was extracted with EtOAc (2×), the combined organics were dried (MgSO₄) and the volatiles removed to give a crude residue that was purified via chromatography (0-5% MeOH/DCM) to yield 89 mg (67%) of the title compound. MS (ESI) m/z 382 (MH⁺).

Example 104. Preparation of N-(5-chloro-3-propyl-3H-imidazo[4,5-b]pyridin-2-yl)-3,3-dimethylbutanamide

A solution of N-(3-allyl-5-chloro-3H-imidazo[4,5-b]pyridin-2-yl)-3,3-dimethylbutanamide (42 mg, 0.14 mmol, 1 eq) in dry acetonitrile (3 mL) was allowed to chill in a 0° C. bath for 5 min prior to the addition of 2-nitrobenzenesulfonylchloride (91 mg, 0.41 mmol, 3 eq) in one portion. After an additional 5 min, hyrazine hydrate (0.10 mL, 0.82 mmol, 6 eq) was added via syringe. The reaction flask was allowed to slowly warm to room temperature and the reaction was allowed to stir for 18 h prior to the addition of water (10 mL). The mixture was extracted with EtOAc (3 times) and the combined organics were washed with brine. The organic layer was dried with Na₂SO₄ and concentrated to give 50 mg of a crude material. Purification by column chromatography (50-100% EtOAc/hexane) provided the title compound (24 mg, 57% yield). MS (ESI) m/z 309 (MH⁺).

Example 118. Preparation of N-(5-chloro-3-propyl-3H-imidazo[4,5-b]pyridin-2-yl)-3-cyclopentylpropanamide

The title compound was made in an analogous manner to Example 104, but with N-(3-allyl-5-chloro-3H-imidazo[4,5-b]pyridin-2-yl)-3-cyclopentylpropanamide as the starting material.

Example 192. Preparation of N-(5-chloro-3-((1r,3r)-3-fluorocyclobutyl)-3H-imidazo[4,5-b]pyridin-2-yl)-3,3-dimethylbutanamide

To a solution of triethylamine trihydrofluoride (67 mg, 0.41 mmol, 2 eq) in dichloromethane (2 mL) at −78° C. were successively added triethylamine (0.1 mL), XtalFluor-E (71 mg, 0.31 mmol, 1.5 eq) and a solution of N-(5-chloro-3-((1s,3s)-3-hydroxycyclobutyl)-3H-imidazo[4,5-b]pyridin-2-yl)-3,3-dimethylbutanamide (70 mg, 0.20 mmol, 1 eq) in dry dichloromethane. The reaction was allowed to stir at −78° C. for 5 min and then allowed to warm to room temperature and stirred for 3 h before it was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3 times). The combined organics were washed with brine, dried over Na₂SO₄ and concentrated to give 70 mg of a crude material. Purification by column chromatography (50-100% EtOAc/hexane) provided the title compound (5 mg, 7% yield). The material was further purified by reverse phase HPLC (water and acetonitrile, 0.1% TFA buffer, 5 to 100% gradient) to give 2.1 mg of product as a white solid after extraction from sodium carbonate and DCM. M+1=339.2.

General Analytical Methods

HPLC Method A.

Instrument: Agilent 1100 with MSD Column: Ascentis Express C18, 10 cm×4.6 mm×2.7 mm Solvent A: 10 mM ammonium acetate in water Solvent B: 10 mM ammonium acetate in acetonitrile Flow rate: 1.8 mL/min

Method:

0-6.0 min, gradient from B=5% to B=95% 6.0-8.0 min, hold B=95% 8.0-8.1 min, gradient from B=95% to B=5% 8.1-10.0 min, hold B=5%

HPLC Method B.

Instrument: Agilent 1100 with MSD Column: Ascentis Express C18, 10 cm×4.6 mm×2.7 mm Solvent A: 10 mM ammonium acetate in water Solvent B: 10 mM ammonium acetate in acetonitrile Flow rate: 1.8 mL/min

Method:

0-2.5 min, gradient from B=5% to B=95% 2.5-3.0 min, hold B=95% 3.0-3.1 min, gradient from B=95% to B=5% 3.1-5.0 min, hold B=5%

HPLC Method C.

Instrument: Shimadzu LC-8A

Column: Luna C18 (2), 10 cm×4.6 mm, 5 micron Solvent A: 0.05% TFA in water Solvent B: 0.05% TFA in acetonitrile Flow rate: 2 mL/min

Method:

0-10 min, gradient from B=5% to B=95% 10-15 min, hold B=95%

HPLC Method D.

Instrument: Varian Star #1

Column: Luna C18 (2), 25 cm×4.6 mm, 5 micron Solvent A: 0.05% TFA in water Solvent B: 0.05% TFA in acetonitrile Flow rate: 1.15 mL/min

Method:

0-20 min, gradient from B=10% to B=100% 20-25 min, hold B=100%

HPLC Method E.

Instrument: Agilent 1100 with MSD Column: Ascentis Express C18, 10 cm×4.6 mm×2.7 mm Solvent A: 0.1% formic acid in water

Solvent B: Acetonitrile

Flow rate: 1.4 mL/min

Method:

0-3.0 min gradient from B=10% to B=95% 3.0-4.0 min, hold B=95% 4.0-4.2 min, gradient from B=95% to B=10% 4.2-6.0 min, hold B=10%

HPLC Method AA.

Instrument: Varian 500 Integration at 230 or 254 nm

Column: YMS ODS-AQ, 150×4.6 mm, 5 micron

Solvent A: H₂O w/0.05% TFA Solvent B: CH₃CN w/0.05% TFA

Flow rate: 1.0 mL/min

Method:

0 minutes: 90% A, 10% B 10 minutes: 0% A, 100% B 19 minutes: 0% A, 100% B

HPLC Method BB.

Instrument: Varian 500 Integration at 230 or 254 nm

Column: Phenonmenex Luna C18(2) column, 250×4.6 mm, 5 micron

Solvent A: H₂O w/0.025% TFA Solvent B: CH₃CN w/0.025% TFA

Flow rate: 1.2 mL/min

Method:

0 minutes: 90% A, 10% B 10 minutes: 0% A, 100% B 20 minutes: 0% A, 100% B

HPLC Method CC.

Instrument: Varian 500 Integration at 230 or 254 nm

Column: Phenonmenex Luna C18(2) column, 250×4.6 mm, 5 micron

Solvent A: H₂O w/0.1% TFA Solvent B: CH₃CN w/0.1% TFA

Flow rate: 1.0 mL/min

Gradient:

0 minutes: 90% A, 10% B 10 minutes: 5% A, 95% B 16 minutes: 5% A, 95% B

TABLE 1 List of Examples, Synthetic Routes and Analytical Data LC/MS Method of Reten- Synthesis; tion Ex. Coupling HPLC time m/Z No. Structure Name partner Method (min) (MH+) 1

  C₁₈H₂₄N₄O₂ N-(3-cyclobutyl- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (5,5- dimethyltetrahydro- furan-2- yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4, 4451 B 2.8 329 2

  C₁₉H₂₆N₄O₂ (R)-N-(3- cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)-2-(6,6- dimethyltetrahydro- 2H-pyran-2- yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4, 4451 B 3 343 3

  C₁₇H₂₄N₄O₂ 3-(tert-butoxy)-N- (3-cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)propanamide Procedure A; commercial B 2.8 317 4

  C₁₉H₂₆N₄O₂ N-(3-cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)-2-(2,2- dimethyltetrahydro- 2H-pyran-4- yl)acetamide Procedure A; commercial B 2.7 343 5

  C₁₉H₂₆N₄O₂ N-(3-cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)-2-(6,6- dimethyltetrahydro- 2H-pyran-2- yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4, 4451 B 3 343 6

  C₁₅H₁₃ClF₆N₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)-4,4,4-trifluoro- 3-(trifluorometh- yl)butanamide Procedure A; commercial B 3.8 415 7

  C₁₆H₂₁ClN₄O₂ 2-(tert-butoxy)-N-(5- chloro-3-cyclobutyl- 3H-imidazo[4,5- b]pyridin-2- yl)acetamide Procedure A; commercial B 3.2 337 8

  C₂₂H₂₇ClN₄O 2-(adamantan-1-yl)- N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)acetamide Procedure A; commercial B 4.1 399 9

  C₁₉H₂₃ClN₄O 2- (bicyclo[2.2.1]hept- an-2-yl)-N-(5- chloro-3- cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)acetamide Procedure A; commercial B 3.7 359 10

  C₁₉H₂₅ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)-2-(6,6- dimethyltetrahydro- 2H-pyran-2- yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4, 4451 B 3.4 377 11

  C₁₈H₂₃ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)-2-(5,5- dimethyltetrahydro- furan-2- yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4, 4451 B 3.2 363 12

  C₁₉H₂₅ClN₄O₂ (R)-N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)-2-(6,6- dimethyltetrahydro- 2H-pyran-2- yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4, 4451 B 3.4 377 13

  C₁₇H₂₁ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (tetrahydro-2H- pyran-4- yl)acetamide Procedure A; commercial B 2.8 349 14

  C₁₇H₂₃ClN₄O₂ 3-(tert-butoxy)-N- (5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; commercial B 3.2 351 15

  C₁₉H₂₅ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (2,2- dimethyltetrahydro- 2H-pyran-4- yl)acetamide Procedure A; commercial B 3 377 16

  C₁₆H₁₉ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (tetrahydrofuran-3- yl)acetamide Procedure A; commercial B 2.7 335 17

  C₁₆H₁₃F₉N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)- 4,4,4-trifluoro-3- (trifluorometh- yl)butanamide Procedure A; commercial B 3.7 449 18

  C₂₀H₂₈N₄O₃ N-(3-cyclobutyl-5- methoxy-3H- imidazo[4,5- b]pyridin-2-yl)-2- (2,2- dimethyltetrahydro- 2H-pyran-4- yl)acetamide Procedure A; commercial B 2.9 373 19

  C₁₇H₂₂N₄O₃ N-(3-cyclobutyl-5- methoxy-3H- imidazo[4,5- b]pyridin-2-yl)-2- (tetrahydrofuran-3- yl)acetamide Procedure A; commercial B 2.6 331 20

  C₂₀H₂₈N₄O₃ N-(3-cyclobutyl-5- methoxy-3H- imidazo[4,5- b]pyridin-2-yl)-2- (6,6- dimethyltetrahydro- 2H-pyran-2- yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4, 4451 B 3.3 373 21

  C₁₈H₁₇FN₄O N-(3-cyclobutyl- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (4-fluoro- phenyl)acetamide Procedure B; commercial B 3.1 325 22

  C₁₆H₂₂N₄O N-(3-cyclobutyl- 3H-imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure B; commercial B 3 287 23

  C₁₉H₂₀N₄O N-(3-cyclobutyl- 3H-imidazo[4,5- b]pyridin-2-yl)-3- phenylpropanamide Procedure B; commercial B 3.1 321 24

  C₂₁H₂₈N₄O N-(3-cyclobutyl- 3H-imidazo[4,5- b]pyridin-2-yl)-2- ((1S,2S,5S)-6,6- dimethylbi- cyclo[3.1.1]heptan- 2-yl)acetamide Procedure B; US Pat. Appl. 20120122890 B 3.9 353 25

  C₁₆H₂₁ClN₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure B; commercial A 5.5 321 26

  C₁₈H₁₆ClFN₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (4- fluorophenyl)acet- amide Procedure B; commercial A 4.1 259 27

  C₁₈H₂₃ClN₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- cyclopentylpropan- amide Procedure B; commercial A 6.2 347 28

  C₁₅H₁₉ClN₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- methylbutanamide Procedure B; commercial B 3.2 307 29

  C₁₈H₂₃ClN₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- cyclohexylacetamide Procedure B; commercial B 3.6 347 30

  C₁₉H₁₉ClN₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- phenylpropanamide Procedure B; commercial B 3.5 355 31

  C₁₈H₁₇ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- phenoxyacetamide Procedure B; commercial B 3.5 357 32

  C₁₄H₁₇ClN₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2- yl)isobutyramide Procedure B; commercial B 3 293 33

  C₂₁H₂₇ClN₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- ((1S,2S,5S)-6,6- dimethylbicyclo[3. 1.1]heptan-2- yl)acetamide Procedure B; US Pat. App1. 20120122890 B 4.1 385.2 (M−H)− 34

  C₁₄H₁₇ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- ethoxyacetamide Procedure B; commercial B 3 309 35

  C₁₉H₁₉ClN₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- phenylpropanamide Procedure B; commercial B 3.3 355 36

  C₁₆H₂₃ClN₄O N-(5-chloro-3- isobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure B; commercial B 3.3 323 37

  C₁₈H₁₈ClFN₄O N-(5-chloro-3- isobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (4- fluorophenyl)acet- amide Procedure B; commercial B 3.3 361 38

  C₁₅H₂₁ClN₄O N-(5-chloro-3- isobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- methylbutanamide Procedure B; commercial B 3.1 309 39

  C₁₇H₂₁F₃N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure B; commercial A 6 355 40

  C₁₉H₁₆F₄N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (4- fluorophenyl)acet- amide Procedure B; commercial A 6 393 41

  C₁₉H₂₃F₃N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- cyclopentylpropan- amide Procedure B; commercial A 6.6 381 42

  C₁₆H₁₉F₃N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- methylbutanamide Procedure B; commercial A 5.6 341 43

  C₁₉H₂₃F₃N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- cyclohexylacetamide Procedure B; commercial A 6.4 381 44

  C₂₀H₁₉F₃N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- phenylpropanamide Procedure B; commercial A 6.2 389 45

  C₁₉H₁₇F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- phenoxyacetamide Procedure B; commercial A 6.1 391 46

  C₁₅H₁₇F₃N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)isobutyramide Procedure B; commercial A 5.4 327 47

  C₂₂H₂₇F₃N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- ((1S,2S,5S)-6,6- dimethylbi- cyclo[3.1.1]heptan- 2-yl)acetamide Procedure B; US Pat. Appl. 20120122890 A 7.2 422 48

  C₂₀H₁₉F₃N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- phenylpropanamide Procedure B; commercial B 3.5 389 49

  C₁₇H₂₃F₃N₄O N-(3-isobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure B; commercial B 3.5 357 50

  C₁₉H₁₈F₄N₄O 2-(4-fluorophenyl)- N-(3-isobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)acetamide Procedure B; commercial B 3.5 395 51

  C₁₆H₂₁F₃N₄O N-(3-isobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- methylbutanamide Procedure B; commercial B 3.4 343 52

  C₁₇H₂₁N₅O N-(5-cyano-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure B; commercial B 3.1 312 53

  C₁₆H₁₉N₅O N-(5-cyano-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- methylbutanamide Procedure B; commercial E 3.5 298 54

  C₁₇H₂₄N₄O₂ N-(3-cyclobutyl-5- methoxy-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure B; commercial B 3.2 317 55

  C₁₉H₁₉FN₄O₂ N-(3-cyclobutyl-5- methoxy-3H- imidazo[4,5- b]pyridin-2-yl)-2- (4- fluorophenyl)acet- amide Procedure B; commercial B 3.2 355 56

  C₁₆H₂₂N₄O₂ N-(3-cyclobutyl-5- methoxy-3H- imidazo[4,5- b]pyridin-2-yl)-3- methylbutanamide Procedure B; commercial B 3.1 303 57

  C₁₆H₂₁ClN₄O N-(6-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure B; commercial B 3.4 321 58

  C₁₈H₁₆ClFN₄O N-(6-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (4- fluorophenyl)acet- amide Procedure B; commercial B 3.4 359 59

  C₁₅H₁₉ClN₄O N-(6-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- methylbutanamide Procedure B; commercial B 3.2 307 60

  C₁₇H₂₁F₃N₄O N-(3-cyclobutyl-6- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure C; commercial D 17.5 355 61

  C₂₀H₁₉F₃N₄O N-(3-cyclobutyl-6- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- phenylpropanamide Procedure C; commercial D 17.1 380 62

  C₁₇H₁₆F₃N₅O₂ N-(3-cyclobutyl-6- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (5-methylisoxazol- 3-yl)acetamide Procedure C; commercial D 9.2 381 63

  C₁₉H₂₃F₃N₄O N-(3-cyclobutyl-6- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- cyclopentylpropan- amide Procedure C; commercial C 18.1 389 64

  C₂₀H₂₃F₃N₄O 2-((1S,4R)- bicyclo[2.2.1]hept- an-2-yl)-N-(3- cyclobutyl-6- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)acetamide Procedure D; commercial D 19.1 393 65

  C₁₉H₁₆F₄N₄O N-(3-cyclobutyl-6- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (4- fluorophenyl)acet- amide Example 65; commercial C 8.5 393 66

  C₁₅H₁₆ClF₃N₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)- 3,3,3-trifluoro-2,2- dimethylpropan- amide Procedure A; commercial E 4.7 361 67

  C₁₇H₂₄N₄O N-(3-cyclobutyl-7- methyl-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure B; commercial E 3.4 301 68

  C₁₈H₂₆N₄O₂ 3-(tert-butoxy)-N- (3-cyclobutyl-7- methyl-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; commercial E 3.3 331 69

  C₁₄H₁₆ClF₃N₄O N-(5-chloro-3- (2,2,2- trifluoroethyl)-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 3.8 349 70

  C₁₆H₂₃ClN₄O₂ 3-(tert-butoxy)-N- (5-chloro-3- isopropyl-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; commercial E 3.6 339 71

  C₁₈H₂₅ClN₄O₂ (S)-N-(5-chloro-3- isopropyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (6,6- dimethyltetrahydro- 2H-pyran-2- yl)acetamide Procedure A; Larcheveque M, et al. Tetrahedron, 1990, 46(12), Marotta E, et al. Org Lett, 2002, 4, 4451 E 3.9 365 72

  C₁₅H₁₈ClF₃N₄O₂ 3-(tert-butoxy)-N- (5-chloro-3-(2,2,2- trifluoroethyl)-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; commercial E 3.6 379 73

  C₁₇H₂₀ClF₃N₄O₂ (S)-N-(5-chloro-3- (2,2,2- trifluoroethyl)-3H- imidazo[4,5- b]pyridin-2-yl)-2- (6,6- dimethyltetrahydro- 2H-pyran-2- yl)acetamide Procedure A; Larcheveque M, et al. Tetrahedron, 1990, 46(12), Marotta E, et al. Org Lett, 2002, 4, 4451 E 3.9 405 74

  C₁₅H₂₁ClN₄O N-(5-chloro-3- isopropyl-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 3.8 309 75

  C₁₇H₂₁ClN₄O N-(3-allyl-5-chloro- 3H-imidazo[4,5- b]pyridin-2-yl)-3- cyclopentylpro- panamide Procedure E; commercial E 3.9 333 76

  C₁₅H₁₉ClN₄O N-(3-allyl-5-chloro- 3H-imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure E; commercial E 3.5 307 77

  C₁₆H₂₃ClN₄O N-(3-(tert-butyl)-5- chloro-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 4 323 78

  C₁₇H₂₃ClN₄O₂ N-(5-chloro-3- (tetrahydro-2H- pyran-4-yl)-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 3.4 351 79

  C₁₈H₂₅ClN₄O₂ (R)-3-(tert-butoxy)- N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2- yl)butanamide Procedure A; Balibar CJ, et al. Chem & Biol, 2005, 12(11), 1189. E 4.0 365 80

  C₁₈H₂₅ClN₄O₂ (S)-3-(tert-butoxy)- N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2- yl)butanamide Procedure A; Balibar CJ, et al. Chem & Biol, 2005, 12(11), 1189. E 4.0 365 81

  C₁₇H₂₁ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- (cyclopropylmeth- oxy)propanamide Procedure A; commercial E 3.7 349 82

  C₁₈H₂₆N₄O₂ (S)-3-(tert-butoxy)- N-(3-cyclobutyl- 3H-imidazo[4,5- b]pyridin-2- yl)butanamide Procedure A; Balibar CJ, et al. Chem & Biol, 2005, 12(11), 1189. E 3.3 331 83

  C₁₈H₂₁ClN₄O₂ 2-((1R,2R,4S)-7- oxa- bicyclo[2.2.1]hept- an-2-yl)-N-(5- chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2- yl)acetamide Procedure A; Method 18 E 3.4 361 84

  C₁₈H₂₁ClN₄O₂ 2-((1R,2S,4S)-7- oxa- bicyclo[2.2.1]hept- an-2-yl)-N-(5- chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2- yl)acetamide Procedure A; Method 18 E 3.4 361 85

  C₁₈H₂₃ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (1- hydroxycyclo- hexyl)acetamide Procedure A; commercial E 3.8 363 86

  C₁₈H₂₃ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- (cyclopentyl- oxy)propanamide Procedure A; commercial E 4.0 363 87

  C₁₈H₂₃F₃N₄O₂ 3-(tert-butoxy)-N- (3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; commercial E 4 385 88

  C₂₀H₂₅F₃N₄O₂ (R)-N-(3- cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (6,6- dimethyltetrahydro- 2H-pyran-2- yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4, 4451 E 4.3 411 89

  C₁₇H₂₁F₃N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- methylpentanamide Procedure A; commercial E 4.3 355 90

  C₁₉H₂₃F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (1-hydroxycyclo- hexyl)acetamide Procedure A; commercial E 4 397 91

  C₁₉H₂₃F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- (cyclopentyl- oxy)propanamide Procedure A; Method 20 E 4.2 397 92

  C₁₉H₂₅F₃N₄O₂ (S)-3-(tert-butoxy)- N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)butanamide Procedure A; Balibar CJ, et al. Chem & Biol, 2005, 12(11), 1189. E 4.2 399 93

  C₁₉H₂₅F₃N₄O₂ (R)-3-(tert-butoxy)- N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)butanamide Procedure A; Balibar CJ, et al. Chem & Biol, 2005, 12(11), 1189. E 4.2 399 94

  C₁₆H₁₆F₆N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- (2,2,2- trifluoroethoxy)pro- panamide Procedure A; commercial E 3.9 411 95

  C₁₇H₂₁F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- isopropoxypropan- amide Procedure A; Method 20 E 3.9 371 96

  C₁₉H₂₃F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (5,5- dimethyltetrahydro- furan-2- yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4, 4451 E 4 397 97

  C₁₇H₂₅ClN₄O₂ 3-(tert-butoxy)-N- (3-(tert-butyl)-5- chloro-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; commercial E 3.8 353 98

  C₁₉H₂₇ClN₄O₂ (R)-N-(3-(tert- butyl)-5-chloro-3H- imidazo[4,5- b]pyridin-2-yl)-2- (6,6- dimethyltetrahydro- 2H-pyran-2- yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4, 4451 E 4 379 99

  C₁₈H₂₅ClN₄O₃ 3-(tert-butoxy)-N- (5-chloro-3- (tetrahydro-2H- pyran-4-yl)-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; commercial E 3.3 381 100

  C₁₆H₂₁ClN₄O₂ N-(3-allyl-5-chloro- 3H-imidazo[4,5- b]pyridin-2-yl)-3- (tert- butoxy)propanamide Procedure A; commercial E 3.3 337 101

  C₂₂H₃₃ClN₄O₅ 2-(2-(3-(tert- butoxy)propan- amido)-5-chloro- 3H-imidazo[4,5- b]pyridin-3-yl)ethyl 3-(tert- butoxy)propanoate Procedure A; commercial E 3.7 469 102

  C₁₈H₂₃ClN₄O₂ (R)-N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (5,5- dimethyltetrahydro- furan-2- yl)acetamide Procedure A; Hirama M, J Chem Soc, Chem Commun 1983, 599; Marotta E, et al. Org Lett, 2002, 4, 4451 E 3.8 363 103

  C₁₅H₁₆ClF₃N₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- (2,2,2- trifluoroethoxy)pro- panamide Procedure A; commercial E 3.8 377 104

  C₁₅H₂₁ClN₄O N-(5-chloro-3- propyl-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Example 104; commercial E 3.6 309 105

  C₁₈H₁₈ClFN₄O N-(5-chloro-3-(4- fluorophenyl)-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 3.6 361 106

  C₂₁H₂₂ClFN₄O₂ (R)-N-(5-chloro-3- (4-fluorophenyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (6,6- dimethyltetrahydro- 2H-pyran-2- yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4. 4451 E 3.7 417 107

  C₁₇H₂₁F₃N₄O N-(5-cyclopropyl- 3-(2,2,2- trifluoroethyl)-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 4.1 355 108

  C₁₈H₂₃F₃N₄O₂ 3-(tert-butoxy)-N- (5-cyclopropyl-3- (2,2,2- trifluoroethyl)-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure D; commercial E 3.9 385 109

  C₁₉H₂₅ClN₄O₂ (S)-N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (6,6- dimethyltetrahydro- 2H-pyran-2- yl)acetamide Procedure A; Larcheveque M, et al. Tetrahedron, 1990, 46(12), Marotta E, et al. Org Lett, 2002, 4, 4451 E 4.0 377 110

  C₁₆H₂₃ClN₄O₂ 3-(tert-butoxy)-N- (5-chloro-3-propyl- 3H-imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; commercial E 3.4 339 111

  C₁₇H₂₃ClN₄O₂ N-(5-chloro-3- propyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (5,5- dimethyltetrahydro- furan-2-yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4, 4451 E 3.4 351 112

  C₂₀H₂₅F₃N₄O₂ (S)-N-(3- cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (6,6- dimethyltetrahydro- 2H-pyran-2- yl)acetamide Procedure A; Larcheveque M, et al. Tetrahedron, 1990, 46(12), Marotta E, et al. Org Lett, 2002, 4, 4451 E 4.3 411 113

  C₁₉H₂₃F₃N₄O₂ (R)-N-(3- cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (5,5- dimethyltetrahydro- furan-2- yl)acetamide Procedure A; Hirama M, J Chem Soc, Chem Commun 1983, 599; Marotta E, et al. Org Lett, 2002, 4, 4451 E 4 397 114

  C₂₀H₂₃F₃N₄O₃ 3-((1R,2R,4S)-7- oxabi- cyclo[2.2.1]heptan- 2-yloxy)-N- (3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; Method 20 E 3.7 425 115

  C₁₆H₁₆F₆N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)- 4,4,4-trifluoro-3- hydroxy-3- methylbutanamide Procedure A; commercial E 4.1 411 116

  C₁₉H₂₀ClFN₄O₂ 3-(tert-butoxy)-N- (5-chloro-3-(4- fluorophenyl)-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; commercial E 3.5 391 117

  C₁₆H₂₁ClN₄O₃ methyl 3-(5-chloro- 2-(3,3-dimethyl- butanamido)-3H- imidazo[4,5- b]pyridin-3- yl)propanoate Procedure E; commercial E 3.3 353 118

  C₁₇H₂₃ClN₄O N-(5-chloro-3- propyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- cyclopentylpropan- amide Example 118; commercial E 4 335 119

  C₁₅H₂₂Cl₂N₄O₂ N-(5-chloro-3-(2- methoxyethyl)-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide hydrochloride Procedure E; commercial E 3.3 325 120

  C₁₈H₂₅F₃N₄O₃ 3-(tert-butoxy)-N- (5-isopropoxy-3- (2,2,2- trifluoroethyl)-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; commercial E 4.0 403 121

  C₁₇H₂₁ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- (tetrahydrofuran-2- yl)propanamide Procedure A; commercial E 3.4 349 122

  C₁₇H₂₁ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- (tetrahydrofuran-3- yl)propanamide Procedure A; commercial E 3.3 349 123

  C₁₈H₂₃ClN₄O₂ (S)-N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (5,5- dimethyltetrahydro- furan-2- yl)acetamide Procedure A; Larcheveque M, et al. Tetrahedron, 1990,46(12), Marotta E, et al. Org Lett, 2002, 4, 4451 E 3.8 363 124

  C₁₈H₂₁F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- (tetrahydrofuran-3- yl)propanamide Procedure A; commercial E 3.7 383 125

  C₁₈H₂₁F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- (tetrahydrofuran-2- yl)propanamide Procedure A; commercial E 3.6 383 126

  C₁₉H₂₃F₃N₄O₂ (S)-N-(3- cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (5,5- dimethyltetrahydro- furan-2-yl)acetamide Procedure A; Larcheveque M, et al. Tetrahedron, 1990,46(12), Marotta E, et al. Org Lett, 2002, 4, 4451 E 4.02 397 127

  C₁₈H₂₅ClN₄O₂ 3-(tert-butoxy)-N- (5-chloro-3- cyclobutyl-7- methyl-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; commercial E 3.9 365 128

  C₁₇H₂₃ClN₄O N-(5-chloro-3- cyclobutyl-7- methyl-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure B; commercial E 4 335 129

  C₁₈H₁₇Cl₃N₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (3- chlorophenyl)acet- amide hydrochloride Procedure A; commercial E 4.4 375 130

  C₁₇H₂₄Cl₂N₄O₂ N-(5-chloro-3-(2- methoxyethyl)-3H- imidazo[4,5- b]pyridin-2-yl)-3- cyclopentylpropan- amide hydrochloride Procedure E; commercial E 3.7 351 131

  C₁₅H₁₉F₃N₄O 3,3-dimethyl-N-(5- methyl-3-(2,2,2- trifluoroethyl)-3H- imidazo[4,5- b]pyridin-2- yl)butanamide Procedure A; commercial E 3.6 329 132

  C₁₆H₂₁F₃N₄O₂ 3-(tert-butoxy)-N- (5-methyl-3-(2,2,2- trifluoroethyl)-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; commercial E 3.4 359 133

  C₁₇H₂₄N₄O N-(3-cyclobutyl-5- methyl-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 3.5 301 134

  C₁₈H₂₆N₄O₂ 3-(tert-butoxy)-N- (3-cyclobutyl-5- methyl-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure D; commercial E 3.4 331 135

  C₁₅H₁₉F₃N₄O₂ 3-(tert-butoxy)-N- (3-(2,2,2- trifluoroethyl)-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; commercial E 3.2 345 136

  C₁₇H₁₆ClN₅O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (pyridin-2- yl)acetamide Procedure A; commercial E 2.6 342 137

  C₁₈H₂₀Cl₂N₄O N-(5-chloro-3- propyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- phenylpropanamide hydrochloride Procedure C; commercial E 3.7 343 138

  C₂₀H₂₉N₅O₂ N-(3-cyclobutyl-5- morpholino-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure C; commercial CC 9.76 372 139

  C₁₈H₂₁F₃N₄O 3-cyclobutyl-N-(3- cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; commercial E 4.4 367 140

  C₁₇H₂₁F₃N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-4- methylpentanamide Procedure A; commercial E 4.3 355 141

  C₁₉H₁₆ClF₃N₄O 2-(3- chlorophenyl)-N- (3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)acetamide Procedure A; commercial E 4.5 409 142

  C₁₇H₁₉F₃N₄O 2-cyclobutyl-N-(3- cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)acetamide Procedure A; commercial E 4.1 353 143

  C₁₈H₂₃F₃N₄O₂ 3,3-dimethyl-N-(3- (tetrahydro-2H- pyran-3-yl)-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)butanamide Procedure B; commercial E 3.8 385 144

  C₁₉H₂₅F₃N₄O₃ 3-(tert-butoxy)-N- (3-(tetrahydro-2H- pyran-3-yl)-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; commercial E 3.7 415 145

  C₁₉H₂₃ClN₄O₃ 3-((1R,2R,4S)-7- oxa- bicyclo[2.2.1]hept- an-2-yloxy)-N- (5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure D; Method 18 E 3.4 391 146

  C₂₁H₃₁N₅O₃ 3-(tert-butoxy)-N- (3-cyclobutyl-5- morpholino-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure D; commercial CC 9.48 402 147

  C₁₆H₂₄ClN₅O N-(5-amino-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide hydrochloride Example 147; commercial E 2.5 302 148

  C₁₈H₁₈ClN₅O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (6-methylpyridin-2- yl)acetamide Procedure A; commercial E 2.5 356 149

  C₁₇H₂₃ClN₄O N-(5-chloro-3- cyclobutyl-6- methyl-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 4.1 335 150

  C₁₈H₂₂N₄O N-(3-cyclobutyl-5- ethynyl-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure B; commercial E 3.7 311 151

  C₂₁H₂₆ClN₅O N-(3-cyclobutyl-5- (pyridin-3-yl)-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide hydrochloride Example 151; commercial E 2.8 364 152

  C₂₁H₃₁N₅O₃ tert-butyl (3- cyclobutyl-2-(3,3- dimethylbutan- amido)-3H- imidazo[4,5- b]pyridin-5- yl)carbamate Procedure C; commercial CC 10.85 402 153

  C₁₅H₁₈ClF₃N₄O N-(5-chloro-6- methyl-3-(2,2,2- trifluoroethyl)-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 4.0 363 154

  C₁₉H₂₇ClN₄O₂ 3-(tert-butoxy)-N- (5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2,2- dimethylpropan- amide Procedure A; Method 19 E 4.7 379 155

  C₁₈H₂₃F₃N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- ethylpentanamide Procedure A; Mayer SC, et al. J Med Chem 2008, 51, 7348. E 4.5 369 156

  C₁₇H₁₈F₃N₅O₂ 3,3-dimethyl-N-(3- (5-methylisoxazol- 3-yl)-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)butanamide Example 156; commercial E 4 382 157

  C₂₂H₂₇N₅O₂ 3-(tert-butoxy)-N- (3-cyclobutyl-5- (pyridin-3-yl)-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure D; commercial CC 8.05 394 158

  C₁₅H₂₁ClN₄O₂ N-(5-chloro-3- propyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- methoxy-3- methylbutanamide Procedure A; Method 23 E 3.1 325 159

  C₁₆H₂₁ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- methoxy-3- methylbutanamide Procedure A; Method 23 E 3.5 337 160

  C₁₆H₂₁F₃N₄O N-(3-isopropyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 4.1 343 161

  C₁₆H₁₉F₃N₄O 3,3-dimethyl-N-(3- (2,2,2- trifluoroethyl)-5- vinyl-3H- imidazo[4,5- b]pyridin-2- yl)butanamide Procedure D; commercial E 4.0 341 162

  C₁₆H₂₁F₃N₄O N-(5-ethyl-3- (2,2,2- trifluoroethyl)-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Example 162; commercial E 3.9 343 163

  C₁₆H₁₉F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- hydroxy-3- methylbutanamide Procedure A; commercial E 3.4 357 164

  C₁₈H₂₃F₃N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-4,4- dimethylpentan- amide Procedure A; commercial E 4.4 369 165

  C₂₀H₂₇F₃N₄O₂ 3-(tert-butoxy)-N- (3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2,2- dimethylpropan- amide Procedure A; Method 19 E 4.9 413 166

  C₁₈H₂₃F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-4- methoxy-4- methylpentanamide Procedure A; King, SA, J Org Chem, 1994, 59, 2253; base hydrolysis E 3.8 385 167

  C₁₇H₁₈F₆N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)- 4,4,4-trifluoro-3,3- dimethylbutanamide Procedure A; Pat. Appl. WO 2011102964 E 4.5 409 168

  C₁₉H₂₅F₃N₄O₂ (R)-3-(tert-butoxy)- N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- methylpropanamide Procedure A; Method 19 E 4.3 399 169

  C₁₉H₂₅F₃N₄O₂ (S)-3-(tert-butoxy)- N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- methylpropanamide Procedure A; Method 19 E 4.3 399 170

  C₁₈H₂₁F₃N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- cyclopentylacet- amide Procedure A; commercial E 4.3 367 171

  C₁₇H₂₁F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- methoxy-3- methylbutanamide Procedure A; Method 23 E 3.8 371 172

  C₁₉H₂₀F₃N₅O 3,3-dimethyl-N-(3- (6-methylpyridin-3- yl)-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)butanamide Example 172; commercial E 3.3 392 173

  C₁₇H₂₃ClN₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- ethylpentanamide Procedure A; Mayer SC, et al. J Med Chem 2008, 51, 7348. E 4.2 335 174

  C₁₆H₁₈ClF₃N₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)- 4,4,4-trifluoro-3,3- dimethylbutanamide Procedure A; Pat. Appl. WO 2011102964 E 4.4 375 175

  C₁₇H₂₃ClN₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-4,4- dimethylpentan- amide Procedure A; commercial E 4.2 335 176

  C₁₅H₁₉ClN₄O₂ isobutyl (5-chloro- 3-cyclobutyl-3H- imidazo[4,5- b]pyridin-2- yl)carbamate Example 176; commercial E 2.7 323 177

  C₁₇H₁₇ClFN₅O N-(5-chloro-3-(5- fluoropyridin-2-yl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 3.8 362 178

  C₁₇H₂₁ClN₄O₂ N-(6-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- (tetrahydrofuran-2- yl)propanamide Procedure A; commercial E 3.4 349 179

  C₁₉H₂₇ClN₄O₂ 3-(tert-butoxy)-N- (6-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2,2- dimethylpropan- amide Procedure A; Method 19 E 4.8 379 180

  C₁₈H₂₁F₃N₄O₂ N-(3-cyclobutyl-6- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- (tetrahydrofuran-2- yl)propanamide Procedure A; commercial E 3.6 383 181

  C₂₀H₂₇F₃N₄O₂ 3-(tert-butoxy)-N- (3-cyclobutyl-6- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2,2- dimethylpropan- amide Procedure A; Method 19 EE 4.9 413 182

  C₂₁H₂₁F₃N₄O (R)-N-(3- cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- phenylbutanamide Procedure A; commercial E 4.4 403 183

  C₂₁H₂₁F₃N₄O (S)-N-(3- cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- phenylbutanamide Procedure A; commercial E 4.4 403 184

  C₁₇H₁₅F₇N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (2,2,3,3- tetrafluorocyclobut- yl)acetamide Procedure A; commercial E 4.3 425 185

  C₁₈H₁₇F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- (furan-2- yl)propanamide Procedure A; commercial E 4.1 379 186

  C₁₈H₁₇F₃N₄OS N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- (thiophen-2- yl)propanamide Procedure A; commercial E 4.2 395 187

  C₁₇H₁₇F₅N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (3,3- difluorocyclobutyl) acetamide Procedure A; commercial E 4.1 389 188

  C₁₇H₂₁F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-4- methoxypentan- amide Procedure A; King, SA, J Org Chem, 1994, 59, 2253; base hydrolysis E 3.7 371 189

  C₁₈H₁₉ClFN₅O₂ 3-(tert-butoxy)-N- (5-chloro-3-(5- fluoropyridin-2-yl)- 3H-imidazo[4,5- b]pyridin-2- yl)propanamide Procedure D; commercial E 3.6 392 190

  C₂₀H₁₅ClFN₅O N-(5-chloro-3-(5- fluoropyridin-2-yl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- phenylpropanamide Procedure B; commercial E 3.9 396 191

  C₁₇H₂₁F₃N₄O (S)-N-(3- cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- methylpentanamide Procedure A; commercial E 4.2 355 192

  C₁₆H₂₀ClFN₄O N-(5-chloro-3- ((1s,3s)-3- fluorocyclobutyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Example 192; commercial E 3.8 339 193

  C₁₆H₂₃ClN₄O₂ N-(5-chloro-3-(2- ethoxyethyl)-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure A; commercial E 3.5 339 194

  C₁₇H₂₃ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-4- methoxy-4- methylpentanamide Procedure A; US Pat. Appl. 20080019978 E 3.6 351 195

  C₁₆H₁₇ClF₂N₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (3,3- difluorocyclobutyl) acetamide Procedure A; commercial E 3.9 355 196

  C₁₉H₂₆N₄O₂ (S)-N-(3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (6,6- dimethyltetrahydro- 2H-pyran-2- yl)acetamide Procedure A; Larcheveque M, et al. Tetrahedron, 1990, 46(12), Marotta E, et al. Org Lett, 2002, 4, 4451 E 3.4 343 197

  C₁₈H₂₃N₅O₂ N-(5-cyano-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-4- methoxy-4- methylpentanamide Procedure A; US Pat. Appl. 20080019978 E 3.3 342 198

  C₁₆H₂₀Cl₂N₄O N-(5,6-dichloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 4.4 355 199

  C₁₆H₁₉F₃N₄O N-(3-cyclobutyl- 3H-imidazo[4,5- b]pyridin-2-yl)- 4,4,4-trifluoro-3,3- dimethylbutanamide Procedure A; commercial E 4 341 200

  C₁₇H₁₈F₃N₅O N-(5-cyano-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)- 4,4,4-trifluoro-3,3- dimethylbutanamide Procedure A; commercial E 4 366 201

  C₁₇H₁₈F₆N₄O N-(3-cyclobutyl-6- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)- 4,4,4-trifluoro-3,3- dimethylbutanamide Procedure A; commercial E 4.5 409 202

  C₁₆H₁₈ClF₃N₄O N-(6-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)- 4,4,4-trifluoro-3,3- dimethylbutanamide Procedure A; commercial E 4.5 375 203

  C₁₉H₂₅ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- (cyclohexyloxy)pro- panamide Procedure A; Method 20 BB 13.72 377 204

  C₁₆H₂₁ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- methoxy-2,2- dimethylpropan- amide Procedure A; commercial BB 16.94 337 205

  C₁₇H₂₁ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- cyclobutoxypropan- amide Procedure A; Method 20 AA 9.41 349 206

  C₁₉H₂₃ClF₂N₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- ((4,4- difluorocyclohexyl) oxy)propanamide Procedure A; Method 20 AA 9.63 413 207

  C₁₉H₂₃ClN₄O₂ 3-((1R,3r,5S)- bicyclo[3.1.0]hexan- 3-yloxy)-N-(5- chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2- yl)propanamide Procedure A; Method 20 AA 9.84 375 208

  C₁₄H₁₅Cl₂F₃N₄O N-(5,6-dichloro-3- (2,2,2- trifluoroethyl)-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 4.1 383 209

  C₂₁H₂₁F₃N₄O (R)-N-(3- cyclobutyl-6- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- phenylbutanamide Procedure A; commercial E 4.3 403 210

  C₂₁H₂₁F₃N₄O (S)-N-(3- cyclobutyl-6- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- phenylbutanamide Procedure A; commercial E 4.3 403 211

  C₁₉H₁₅Cl₂F₃N₄O N-(3-cyclobutyl-6- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (2,5- dichlorophenyl)acet- amide Procedure A; commercial E 4.8 444 212

  C₁₇H₁₈F₃N₅O₂ 3,3-dimethyl-N-(3- (3-methylisoxazol- 5-yl)-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)butanamide Example 212; commercial E 3.6 382 213

  C₁₆H₁₈ClF₃N₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)- 5,5,5-trifluoro-3- methylpentanamide Procedure A; Pat. Appl. WO 2008024433 AA 10.05 375 214

  C₁₈H₂₁ClF₂N₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (4,4-difluorocy- clohexyl)acetamide Procedure A; commercial AA 9.79 383 215

  C₁₇H₁₆F₃N₅OS N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- (thiazol-2- yl)propanamide Procedure A; commercial E 3.7 396 216

  C₁₇H₂₁F₃N₄O N-(3-cyclobutyl-5- methyl-3H- imidazo[4,5- b]pyridin-2-yl)- 4,4,4-trifluoro-3,3- dimethylbutanamide Procedure A; commercial E 4.4 355 217

  C₁₅H₁₉F₃N₄O₂ N-(5- (hydroxymethyl)-3- (2,2,2- trifluoroethyl)-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Example 217; commercial E 3.0 345 218

  C₁₉H₁₇ClN₆O N-(5-chloro-3-(1- methyl-1H- pyrazol-4-yl)-3H- imidazo[4,5- b]pyridin-2-yl)-3- phenylpropanamide Example 218; commercial E 3.1 381 219

  C₁₈H₁₈F₆N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3-(1- (trifluoromethyl)cy- clopropyl)propanamide Procedure A; Method 22 E 4.3 421 220

  C₁₈H₂₁F₃N₄O₂ (S)-N-(3- cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3- (tetrahydrofuran-2- yl)propanamide Procedure A; Method 22 E 3.7 383 221

  C₂₀H₂₃F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- ((1R,5R)-5-methyl-2- oxabicyclo[3.2.0]hept- an-7-yl)acetamide Procedure A; Method 17 E 4 409 222

  C₂₀H₂₃F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- ((1R,5S)-5-methyl-2- oxabicyclo[3.2.0]hept- an-7-yl)acetamide Procedure A; Method 17 E 4 409 223

  C₁₇H₁₈ClF₃N₄O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3-(1- (trifluoromethyl)cyclo- propyl)propanamide Procedure A; Method 22 E 4.1 387 224

  C₁₇H₂₀ClF₃N₄O N-(6-chloro-3- cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 4.5 389 225

  C₁₈H₂₁F₃N₄O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (2,2-dimethylcyclo- propyl)acetamide Procedure A; Method 16 E 4.3 367 226

  C₂₁H₁₉F₃N₄O 2-(bicyclo[4.2.0]octa- 1(6),2,4-trien-7-yl)- N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2- yl)acetamide Procedure A; Method 24 E 4.4 401 227

  C₂₃H₂₈N₄O₂ N-(5-(benzyloxy)- 3-cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 4.1 393 228

  C₁₈H₂₀F₅N₅O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2-(4,4- difluoropiperidin-1- yl)acetamide Procedure A; Method 21 E 2.6 418 229

  C₁₈H₂₃F₂N₅O N-(3-cyclobutyl-5- methyl-3H- imidazo[4,5- b]pyridin-2-yl)-2-(4,4- difluoropiperidin-1- yl)acetamide Procedure A; Method 21 E 2.4 364 230

  C₂₀H₂₅F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (2,5,5- trimethyltetrahydro- furan-2-yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4, 4451 E 4.2 411 231

  C₁₉H₂₅ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (2,5,5- trimethyltetrahydro- furan-2-yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4, 4451 E 3.9 377 232

  C₂₀H₂₅N₅O₂ N-(5-cyano-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2- (2,5,5- trimethyltetrahydro- furan-2-yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4, 4451 E 3.7 368 233

  C₁₉H₂₆N₄O₂ N-(3-cyclobutyl- 3H-imidazo[4,5- b]pyridin-2-yl)-2- (2,5,5- trimethyltetrahydro- furan-2-yl)acetamide Procedure A; Marotta E, et al. Org Lett, 2002, 4, 4451 E 3.2 343 234

  C₁₇H₂₀ClF₂N₅O N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-2-(3,3- difluoropiperidin-1- yl)acetamide Procedure A; Method 21 E 2.7 384 235

  C₁₈H₂₀F₅N₅O N-(3-cyclobutyl-5- (trifluoromethyl)- 3H-imidazo[4,5- b]pyridin-2-yl)-2-(3,3- difluoropiperidin-1- yl)acetamide Procedure A; Method 21 E 2.9 418 236

  C₁₇H₁₂D₉F₃N₄O Procedure B; Oonishi Y, Angew Chemie, IEE 2012, 51(29), 7305 E 4.2 364 237

  C₁₉H₂₅ClN₄O₂ N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5- b]pyridin-2-yl)-3- (cyclopentyloxy)butan- amide Procedure A; Harschneck T, et al., J Org Chem 2001, 76, 2145; Method 20 AA 10.51 377 238

  C₁₉H₂₃ClN₄O₂ 3-((1R,3s,5S)- bicyclo[3.1.0]hexan- 3-yloxy)-N-(5-chloro- 3-cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)propanamide Procedure A; Method 20 AA 10.61 375 239

  C₁₆H₂₀N₆O₂ 3,3-dimethyl-N-(5- methyl-3-(5-methyl- 1,3,4-oxadiazol-2-yl)- 3H-imidazo[4,5- b]pyridin-2- yl)butanamide Procedure B; commercial E 2.9 329 240

  C₂₂H₂₇N₅O₂ N-(3-cyclobutyl-5- (pyridin-2-ylmethoxy)- 3H-imidazo[4,5- b]pyridin-2-yl)-3,3- dimethylbutanamide Procedure D; commercial E 2.9 394 241

  C₁₇H₁₄F₅N₅O₂ 2-(3,3- difluorocyclobutyl)-N- (3-(3-methylisoxazol- 5-yl)-5- (trifluoromethyl)-3H- imidazo[4,5-b]pyridin- 2-yl)acetamide Example 241; commercial E 3.5 416 242

  C₂₁H₂₈N₆O₂ N-(3-cyclobutyl-5-((1- methyl-1H-pyrazol-5- yl)methoxy)-3H- imidazo[4,5-b]pyridin- 2-yl)-3,3- dimethylbutanamide Procedure B; commercial E 3.2 397 243

  C₁₇H₂₀F₂N₄O₂ N-(3-cyclobutyl-7- methoxy-3H- imidazo[4,5-b]pyridin- 2-yl)-2-(3,3- difluorocyclobutyl) acetamide Procedure A; commercial E 3.1 351 244

  C₁₈H₂₂F₂N₄OS N-(3-cyclobutyl-5- (ethylthio)-3H- imidazo[4,5-b]pyridin- 2-yl)-2-(3,3- difluorocyclobutyl) acetamide Procedure A; commercial E 4 381 245

  C₁₇H₁₈F₅N₅O N-(3-cyclobutyl-5- (trifluoromethyl)-3H- imidazo[4,5-b]pyridin- 2-yl)-2-(3,3- difluoropyrrolidin- 1-yl)acetamide Procedure A; Method 21 E 2.8 404 246

  C₁₈H₁₅ClF₄N₄O N-(5-chloro-3-(4- fluorophenyl)-3H- imidazo[4,5-b]pyridin- 2-yl)-4,4,4-trifluoro- 3,3- dimethylbutanamide Procedure A; commercial E 3.8 415 247

  C₁₉H₂₁F₂N₅O N-(5-cyano-3- cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)-2-(4,4- difluorocyclohexyl) acetamide Procedure A; commercial E 3.7 374 248

  C₁₈H₂₁N₅O₂ N-(5-cyano-3- cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)-3-cyclo- butoxypropanamide Procedure A; Method 20 E 3.5 340 249

  C₁₈H₂₄N₄O₂ 3-cyclobutoxy-N- (3-cyclobutyl-5- methyl-3H- imidazo[4,5-b]pyridin- 2-yl)propanamide Procedure A; Method 20 E 3.5 329 250

  C₁₇H₁₇F₂N₅O N-(5-cyano-3- cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)-2-(3,3- difluorocyclobutyl) acetamide Procedure A; commercial E 3.6 346 251

  C₁₇H₂₀F₂N₄O N-(3-cyclobutyl-5- methyl-3H- imidazo[4,5-b]pyridin- 2-yl)-2-(3,3- difluorocyclobutyl) acetamide Procedure A; commercial E 3.7 335 252

  C₁₈H₁₆F₂N₄O N-(3-cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)-2-(3,5- difluorophenyl)acet- amide Procedure A; commercial E 3.9 343 253

  C₁₇H₁₅ClF₂N₄O₂ N-(5-chloro-3-(2- methoxyethyl)-3H- imidazo[4,5-b]pyridin- 2-yl)-2-(3,5- difluorophenyl)acet- amide Procedure A; commercial E 3.6 381 254

  C₁₇H₂₄N₄O₂ N-(3-cyclobutyl-5- methyl-3H- imidazo[4,5-b]pyridin- 2-yl)-3-methoxy-3- methylbutanamide Procedure A; Method 23 E 3 317 255

  C₁₆H₂₂N₄O₂ N-(3-cyclobutyl-5- methyl-3H- imidazo[4,5-b]pyridin- 2-yl)-3-hydroxy-3- methylbutanamide Procedure A; commercial E 2.9 314 256

  C₁₅H₁₄F₆N₄O N-(3-cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)-4,4,4-trifluoro-3- (trifluoromethyl)butan- amide Procedure A; commercial E 4.3 381 257

  C₁₆H₂₁FN₄O₂ N-(3-cyclobutyl-5- fluoro-3H- imidazo[4,5-b]pyridin- 2-yl)-3-methoxy-3- methylbutanamide Procedure A; Method 23 E 3.2 321 258

  C₁₆H₂₁ClN₄O (S)-N-(5-chloro-3- cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)-2,3- dimethylbutanamide Procedure A; Tanasova M, et al., Eur J Org Chem 2012, 3261. E 4 321 259

  C₁₇H₂₁F₃N₄O₂ N-(3-cyclobutyl-5- (trifluoromethyl)-3H- imidazo[4,5-b]pyridin- 2-yl)-4-hydroxy-3,3- dimethylbutanamide Example 259 E 3.5 369 260

  C₁₆H₂₂N₄O (S)-N-(3-cyclobutyl- 3H- imidazo[4,5-b]pyridin- 2-yl)-2,3- dimethylbutanamide Procedure A; Tanasova M, et al., Eur J Org Chem 2012, 3261. E 3.5 287 261

  C₁₇H₂₄N₄O (S)-N-(3-cyclobutyl-5- methyl-3H- imidazo[4,5-b]pyridin- 2-yl)-2,3- dimethylbutanamide Procedure A; Tanasova M, et al., Eur J Org Chem 2012, 3261. E 3.7 301 262

  C₁₇H₂₁F₃N₄O (S)-N-(3-cyclobutyl-5- (trifluoromethyl)-3H- imidazo[4,5-b]pyridin- 2-yl)-2,3- dimethylbutanamide Procedure A; Tanasova M, et al., Eur J Org Chem 2012, 3261. E 4.3 355 263

  C₁₄H₁₆ClF₃N₄O (S)-N-(5-chloro-3- (2,2,2- trifluoroethyl)-3H- imidazo[4,5-b]pyridin- 2-yl)-2,3- dimethylbutanamide Procedure A; Tanasova M, et al., Eur J Org Chem 2012, 3261. E 3.8 349 264

  C₁₈H₁₇F₄N₅O N-(3-(5- fluoropyridin-2-yl)-5- (trifluoromethyl)-3H- imidazo[4,5-b]pyridin- 2-yl)-3,3- dimethylbutanamide Procedure A; commercial E 4 396 265

  C₁₇H₁₅F₄N₅O₂ N-(3-(5- fluoropyridin-2-yl)-5- (trifluoromethyl)-3H- imidazo[4,5-b]pyridin- 2-yl)-3-hydroxy-3- methylbutanamide Procedure A; commercial E 3.2 398 266

  C₁₈H₁₇F₄N₅O (S)-N-(3-(5- fluoropyridin-2-yl)-5- (trifluoromethyl)-3H- imidazo[4,5-b]pyridin- 2-yl)-2,3- dimethylbutanamide Procedure A; Tanasova M, et al., Eur J Org Chem 2012, 3261. E 4 396 267

  C₁₈H₁₃F₆N₅O 2-(3,3- difluorocyclobutyl)- N-(3-(5- fluoropyridin-2-yl)-5- (trifluoromethyl)-3H- imidazo[4,5-b]pyridin- 2-yl)acetamide Procedure A; commercial E 3.8 430 268

  C₁₇H₂₁N₅O (S)-N-(5-cyano-3- cyclobutyl-3H- imidazo[4,5-b]pyridin- 2-yl)-2,3- dimethylbutanamide Procedure A; Tanasova M, et al., Eur J Org Chem 2012, 3261. E 3.8 312 269

  C₁₇H₁₅F₆N₅O₂ 4,4,4-trifluoro-3,3- dimethyl-N-(3-(3- methylisoxazol-5-yl)- 5- (trifluoromethyl)-3H- imidazo[4,5-b]pyridin- 2-yl)butanamide Example 269; commercial E 3.7 436 270

  C₁₆H₁₈F₃N₇O 3,3-dimethyl-N-(3- (1-methyl-1H- 1,2,3-triazol-4-yl)-5- (trifluoromethyl)-3H- imidazo[4,5-b]pyridin- 2-yl)butanamide Procedure A; commercial E 3.4 382 271

  C₂₂H₃₃N₅O₂ N-(3-cyclobutyl-5-(4- methoxypiperidin-1- yl)-3H- imidazo[4,5-b]pyridin- 2-yl)-3,3- dimethylbutanamide Procedure A; commercial E 3 400

The following is a listing of embodiments that are specifically contemplated herein.

Embodiment 1

A compound represented by a formula:

wherein A is optionally substituted 1H-imidazo[4,5-b]pyridin-2-yl or optionally substituted 3H-imidazo[4,5-b]pyridin-2-yl;

L is CH₂, CF₂, C₂H₄, C₃H₆, O, CH₂O, C₂H₄O, or C₃H₆O;

R¹ is C₁₋₁₂ optionally substituted alkyl, C₁₋₁₂ optionally substituted —O-alkyl, optionally substituted C₆₋₁₀ aryl, optionally substituted C₆₋₁₀—O-aryl, or optionally substituted C₂₋₉ heterocyclyl;

wherein the compound is active at a K_(V)7.2 bearing potassium channel, a K_(V)7.3 bearing potassium channel, a K_(V)7.4 bearing potassium channel, or a K_(V)7.5 bearing potassium channel.

Embodiment 2

A compound represented by a formula:

wherein A is optionally substituted 1H-imidazo[4,5-b]pyridin-2-yl or optionally substituted 3H-imidazo[4,5-b]pyridin-2-yl;

L is CH₂, CF₂, C₂H₄, C₃H₆, O, CH₂O, C₂H₄O, or C₃H₆O;

and

R¹ is CH₃, C₂₋₁₂ optionally substituted alkyl, C₁₋₁₂ optionally substituted —O-alkyl, optionally substituted C₆₋₁₀ aryl, optionally substituted C₆₋₁₀—O-aryl, or optionally substituted C₂₋₉ heterocyclyl.

Embodiment 3

The compound of embodiment 1 or 2, wherein the compound is active at a homotetrameric K_(V)7.2 bearing potassium channel, a K_(V)7.3 homotetrameric bearing potassium channel, a heterotetrameric K_(V)7.2/7.3 bearing channel, a heterotetrameric K_(V)7.3/7.5 bearing channel, a homotetrameric K_(V)7.4 bearing potassium channel, or a homotetrameric K_(V)7.5 bearing potassium channel at a concentration below about 10 μM.

Embodiment 4

The compound of any preceding embodiment, further represented by a formula:

wherein R² is —R^(a)-Cy, wherein R^(a) is a bond or C₁₋₁₂ optionally substituted alkyl, and Cy is H, optionally substituted C₆₋₁₀ aryl, or optionally substituted C₂₋₉ heterocyclyl.

Embodiment 5

The compound of any preceding embodiment, wherein the compound has a molecular weight of less than 1500 g/mol.

Embodiment 6

The compound of any preceding embodiment, wherein any substituent present in the compound independently has a molecular weight of 15 g/mol to 200 g/mol.

Embodiment 7

The compound of any of embodiments 4-6, wherein all substituents of R² are independently C₁₋₆ alkyl, C₁₋₆—O-alkyl, OH, F, Cl, Br, I, C₁₋₆ amino, C₁₋₆ aminoalkyl, C₁₋₆ aminoacyl, C₁₋₆ acylamino, C₁₋₆ alkythio, or C₁₋₆ alkylsulfonyl.

Embodiment 8

The compound of any preceding embodiment, further represented by a formula:

Wherein n is 1, 2, or 3, R³, R⁴, and R⁵ are independently H, F, Cl, Br, I, CN, C₁₋₁₂ optionally substituted alkyl, C₁₋₁₂ optionally substituted —O-alkyl, optionally substituted C₂₋₉ heterocyclyl, optionally substituted C₆₋₁₀ aryl, optionally substituted C₂₋₉—O-heterocyclyl, optionally substituted C₆₋₁₀—O-aryl, C₁₋₁₂ optionally substituted acylamino, C₁₋₁₂ optionally substituted aminoacyl, or optionally substituted C₁₋₁₂ aminoalkyl.

Embodiment 9

The compound of embodiment 7, wherein all substituents of R³, R⁴, and R⁵ are independently F, Cl, Br, I, CN, C₁₋₆ alkyl, C₁₋₆—O-alkyl, C₁₋₆ amino, C₁₋₆ aminoalkyl, C₁₋₆ aminoacyl, C₁₋₆ acylamino, C₁₋₆ alkylthio, or C₁₋₆ alkylsulfonyl.

Embodiment 10

The compound of any of embodiments 4-9, wherein R² is cyclobutyl.

Embodiment 11

The compound of any of embodiments 4-9, wherein R² is —CH₂CH(CH₃)₂.

Embodiment 11a

The compound of any of embodiments 4-9, wherein R² triazolyl.

Embodiment 11b

The compound of any of embodiments 4-9, wherein R² oxadiazolyl.

Embodiment 11c

The compound of any of embodiments 4-9, wherein R²isoxazolyl.

Embodiment 12

The compound of any of embodiments 2-11c, wherein R¹ is optionally substituted phenyl.

Embodiment 13

The compound of any of embodiments 2-11c, wherein R¹ is C₃₋₄ alkyl.

Embodiment 14

The compound of any of embodiments 2-11c, wherein R¹ is optionally substituted bicyclo[2.2.1]heptan-2-yl.

Embodiment 15

The compound of any of embodiments 2-11c, wherein R¹ is optionally substituted isoxazol-3-yl.

Embodiment 16

The compound of any of embodiments 2-11c, wherein R¹ is CF₃.

Embodiment 17

The compound of any of embodiments 2-11c, wherein R¹ is optionally substituted cyclopentyl.

Embodiment 18

The compound of any of embodiments 2-11c, wherein R¹ is optionally substituted cyclohexyl.

Embodiment 19

The compound of any of embodiments 2-11c, wherein R¹ is methyl.

Embodiment 20

The compound of any of embodiments 2-11c, wherein R¹ is optionally substituted bicyclo[3.1.1]heptan-2-yl.

Embodiment 21

The compound of any of embodiments 2-11c, wherein R¹ is optionally substituted —O-phenyl.

Embodiment 22

The compound of any of embodiments 2-11c, wherein R¹ is optionally substituted CH(CF₃)₂.

Embodiment 23

The compound of any of embodiments 2-11c, wherein R¹ is C₂₋₄—O-alkyl.

Embodiment 24

The compound of any of embodiments 2-11c, wherein R¹ is optionally substituted adamantan-1-yl.

Embodiment 25

The compound of any of embodiments 2-11c, wherein R¹ is optionally substituted tetrahydro-2H-pyranyl.

Embodiment 26

The compound of any of embodiments 2-11c, wherein R¹ is optionally substituted tetrahydrofuranyl.

Embodiment 27

The compound of any of embodiments 8-26, wherein R³ is CF₃.

Embodiment 28

The compound of any of embodiments 8-26, wherein R³ is Cl.

Embodiment 29

The compound of any of embodiments 8-26, wherein R³ is CN.

Embodiment 30

The compound of any of embodiments 8-26, wherein R³ is OCH₃.

Embodiment 31

The compound of any of embodiments 8-26, wherein R³ is H.

Embodiment 32

The compound of any of embodiments 8-31, wherein R⁴ is CF₃.

Embodiment 33

The compound of any of embodiments 8-31, wherein R⁴ is Cl.

Embodiment 34

The compound of any of embodiments 8-31, wherein R⁴ is H.

Embodiment 35

The compound of embodiment 4, wherein Cy is H and R^(a) is substituted with a CF₃ substituent.

Embodiment 36

The compound of embodiments 1-9, and 12-35, wherein R² is —CH₂CH═CH₂

Embodiment 37

The compound of embodiments 1-9, and 12-35, wherein R² is —CH₂CF₃

Embodiment 38

The compound of embodiments 1-9, and 12-35, wherein R² is —C(CH₃)₃

Embodiment 39

The compound of embodiment 1, further represented by a formula:

Embodiment 40

A composition comprising a compound of any of embodiments 1-39, wherein the composition is pharmaceutically acceptable.

Embodiment 41

A pharmaceutical dosage form comprising a compound of any of embodiments 1-39.

Embodiment 42

A method of treating a disorder associated with a K_(V)7 potassium channel activator comprising administering an effective amount of a compound of any of embodiments 1-39 to a mammal in need thereof.

Embodiment 43

The method of embodiment 42, wherein the disorder is epilepsy, pain, migraine, a disorder of neurotransmitter release, a smooth muscle contractility disorder, a dyskinesia, dystonia, mania, or a hearing disorder.

Embodiment 44

The method embodiment 42, wherein the disorder is epilepsy, neuropathic pain, inflammatory pain, persistent pain, cancer pain, postoperative pain, migraine, anxiety, substance abuse, schizophrenia, a bladder disorder, a vasculature disorder, a dyskinesia, dystonia, mania, a hearing disorder, or tinnitus.

Biological Assay Methods K_(v)7.2/7.3 Activation Assay

The ability of compounds to potentiate K-currents in K_(V)7.2/7.3 containing HEK cells was assessed using planar patch-clamp on the QPatch automated screening platform.

Cell Line:

The hK_(V)7.2/7.3 cell line was obtained from Chantest (Cleveland, Ohio 44128) cat.# CT6147. These HEK cells will express the K_(v)7.2/7.3 ion channels when induced.

Cell Culture: Cells were maintained in a media containing DMEM/F12; 50/50 (GIBCO cat.#11330), 10% Fetal Bovine Serum (FBS) (GIBCO cat.#26140), 100 units/mL Penicillin-Streptomycin (GIBCO cat.#15140), 0.005 mg/mL Blasticidin (INVIVOGEN cat.# ant-bl-1), 0.5 mg/mL Geneticin (GIBCO cat.#10131), 0.1 mg/mL Zeocin (GIBCO cat.# R25001). Cells used in the electrophysiology assay were maintained in a media without Blasticidin, Geneticin and Zeocin for 2 days and channel expression was induced by adding tetracycline (BIOLINE cat.# BIO-87030) at a final concentration of 1 mg/mL. Cells were grown in T-175 flask to ˜75% confluency. Currents were recorded 24 hours after channel induction.

Compound Plates:

Test compounds were prepared by performing serial dilutions on a Biomek NX^(P) (BECKMAN COULTER). Final dilutions were made in external recording solution with a final DMSO concentration of 0.1% DMSO. For single concentration screens each plate had 10 μM retigabine as a positive control and 0.1% DMSO as a negative control.

Electrophysiology:

On the day of the experiment cells were washed with Hank's Balanced Salt Solution (HBBS) (GIBCO cat.#14175) and harvested with Tryple (GIBCO cat.#12604). Cells were then centrifuged at 2000 rpm for 5 minutes and resuspended in CHO-S-SFM (GIBCO cat.#12052) at ˜3×10⁶ cells/mL. Cells were stirred for 30 minutes before experiments were started. External recording solution contained (in mM): NaCl (145), KCl (4), CaCl₂ (2), MgCl₂ (1), HEPES (10) and Glucose (10); pH was adjusted to 7.4 with NaOH and the osmolarity was adjusted to 300-305 mOsM with sucrose if necessary. Internal solution contained (in mM): KCl (125), KF (10), EGTA (5), Na₂ATP (5), MgCl₂ (3.2), HEPES (5); pH was adjusted to 7.2 with KOH and the osmolarity was adjusted to 298-302 mOsM with sucrose.

Potassium channel activity was measured on the QPatch HTX (Sophion Bioscience) using QPlates with 48-wells/plate. Each cell was taken as an independent experiment and only one compound was tested per well. Potassium channel activity was elicited by holding at −80 mV and stepping to −30 mV for 1 s followed by a 100 ms pulse to −120 mV.

Single concentration screen: Baseline conditions were obtained by recording 5 sweeps in the external solution only, this was repeated for three applications of the external solution. The effect of test compounds on elicited current was then assessed by recording 5 sweeps in the presence of a 3 μM or 10 μM compound solution. The steady-state current at the end of the 1 s pulse to −30 mV was measured to determine the fold increase from baseline.

TABLE 2 K_(v)7.2/7.3 Single Concentration Screen Results K_(v)7.2/7.3 Activity K_(v)7.2/7.3 Activity Example Number at 3 μM* at 10 μM* 1 +/− 2 + 3 +++ 4 +/− 5 + + 6 − +/− 7 +/− 8 + 9 +++ 10 + 11 ++ 12 + 13 +/− 14 ++ 15 + 16 +/− 17 +/− 18 + + 19 +/− 20 ++ 21 +/− 22 + ++ 23 + 24 +++ +++ 25 + ++ 26 +/− 27 +++ 28 + +++ 29 +++ 30 + 31 +/− 32 +/− 33 +++ 34 − 35 ++ +++ 36 +++ 37 +/− 38 +/− 39 ++ +++ 40 ++ 41 + 42 + +++ 43 + +++ 44 + 45 +/− 46 + 47 +++ 48 + 49 + 50 +/− 51 +/− + 52 + +/− 53 +/− + 54 ++ 55 + ++ 56 ++ 57 +/− + 58 − + 59 +/− 60 + 61 + + 62 +/− 63 ++ 64 + 65 + + 66 + 67 ++ 68 ++ 69 + 70 + 71 + 72 ++ 73 + 74 +/− 75 + 76 + 77 + 78 + 79 +/− 80 +/− ++ 81 + 82 +/− 83 + 84 +/− 85 + 86 + 87 ++ 88 + + 89 + 90 + + 91 +++ 92 ++ 93 + + 94 +/− 95 ++ 96 +++ 97 + 98 + 99 +/− 100 + 101 +/− 102 + + 103 +/− + 104 + + 105 + +++ 106 +/− 107 + 108 +++ ++ 109 + ++ 110 + 111 +/− + 112 + ++ 113 +/− + 114 + + 115 + + 116 + + 117 +/− +/− 118 + ++ 119 +/− 120 ++ +++ 121 + + 122 +/− 123 + ++ 124 + +++ 125 + + 126 ++ ++ 127 + + 128 + ++ 129 + 130 + + 131 + ++ 132 + +++ 133 ++ ++ 134 ++ ++ 135 + + 136 +/− 137 + 138 + + 139 + + 140 + + 141 +/− 142 +/− 143 +/− 144 + 145 +/− 146 ++ 147 +/− 148 +/− 149 + 150 +/− 151 − 152 +/− 153 + 154 + + 155 ++ 156 ++ 157 +/− 158 +/− 159 + 160 + 161 +/− 162 + 163 + 164 + 165 + ++ 166 + 167 + 168 + 169 + 170 + 171 ++ 172 +/− 173 +/− 174 + 175 +/− 176 +/− 177 + 178 +/− 179 +/− 180 +/− 181 +/− 182 + 183 +/− 184 +/− 185 +/− 186 + 187 +/− 188 +/− 189 +/− 190 + 191 + 192 +/− 193 +/− 194 +/− 195 + + 196 ++ ++ 197 +/− 198 + 199 +/− 200 +/− 201 +/− 202 +/− 203 + 204 +/− 205 + 206 +/− 207 +/− 208 +/− +/− 209 +/− 210 +/− 211 +/− 212 + + 213 +/− 214 + 215 +/− 216 + 217 +/− 218 +/− 219 +/− 220 + 221 + 222 +/− 223 − 224 +/− +/− 225 + 226 +/− 227 + 228 +/− 229 +/− 230 + 231 + 232 +/− 233 +/− 234 +/− 235 + 236 ++ 237 ++ 238 + 239 +/− 240 + 241 + 242 +/− 243 +/− 244 + 245 +/− 246 +/− + 247 +/− 248 + 249 + 250 +/− 251 + 252 +/− 253 +/− 254 + 255 +/− 256 +/− 257 + 258 ++ 259 +/− 260 +/− 261 + 262 ++ 263 + 264 ++ 265 +/− 266 + 267 +/− 268 + 269 +/− 270 + 271 + *Increase in current from K_(v)7.2/K_(v)7.3 co-expressing HEK cells, measured at compound concentration of 3 or 10 μM, as a range from <1.2-fold increase over baseline (−) up to >6-fold increase over baseline (+++).

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

The terms “a,” “an,” “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

Certain embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

In closing, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to embodiments precisely as shown and described. 

1.-40. (canceled)
 41. A compound represented by a formula:

wherein L is CH₂, CHCH₃, CH₂CH₂, C₃H₆, C₂H₄O, or C₃H₆O with the O of C₂H₄₀ or C₃H₆O bonded with R¹; wherein R¹ is optionally substituted C₁₋₂ alkyl, optionally substituted C₅₋₁₀ cycloalkyl, optionally substituted C₁₋₁₂—O-alkyl, optionally substituted C₆₋₁₀ aryl, optionally substituted C₆₋₁₀—O-aryl, or optionally substituted C₂₋₉ heterocyclyl, wherein the optional substituents of R¹ are independently R^(A), F, Cl, CN, OR^(A), CF₃, NR^(A)R^(B), COR^(A), CO₂R^(A), OCOR^(A), NR^(A)COR^(B), CONR^(A)R^(B), wherein R^(A) and R^(B) are independently H or C₁₋₁₂ alkyl; wherein R² is optionally substituted C₂₋₄ acyclic alkyl, optionally substituted cyclobutyl, optionally substituted C₆₋₁₀ aryl, or optionally substituted C₂₋₉ heterocyclyl, wherein the optional substituents of R² are independently F, Cl, Br, I, CN, C₁₋₆ alkyl, C₁₋₆—O-alkyl, C₁₋₆ alkylamine, C₁₋₆ aminoalkyl, C₁₋₆ aminoacyl, C₁₋₆ alkylthio, or C₁₋₆ alkylsulfonyl; wherein R³, R⁴, and R⁵ are independently H, F, Cl, Br, I, CN, optionally substituted C₁₋₁₂ alkyl, optionally substituted C₁₋₁₂—O-alkyl, optionally substituted C₂₋₉ heterocyclyl, optionally substituted C₆₋₁₀ aryl, optionally substituted C₂₋₉—O-heterocyclyl, optionally substituted C₆₋₁₀ O-aryl, optionally substituted C₁₋₁₂ acylamino, optionally substituted C₁₋₁₂ aminoacyl, or optionally substituted C₁₋₁₂ aminoalkyl, wherein the optional substituents of R³, R⁴, or R⁵ are independently F, Cl, Br, I, CN, C₁₋₆ alkyl, C₁₋₆—O-alkyl, C₁₋₆ alkylamine, C₁₋₆ aminoalkyl, C₁₋₆ aminoacyl, C₁₋₆ acylamino, C₁₋₆ alkylthio, or C₁₋₆ alkylsulfonyl.
 42. The compound of claim 41, wherein R¹ is optionally substituted C₁₋₂ alkyl further optionally substituted with: optionally substituted aryl, optionally substituted heterocyclyl, 1-5 fluorine atoms, hydroxyl, or a combination thereof.
 43. The compound of claim 41, wherein R² is optionally substituted C₂₋₄ acyclic alkyl, optionally substituted cyclobutyl, optionally substituted phenyl, or C₂₋₅ optionally substituted heterocyclyl.
 44. The compound of claim 42, wherein R² is optionally substituted C₂₋₄ acyclic alkyl, optionally substituted cyclobutyl, optionally substituted phenyl, or C₂₋₅ optionally substituted heterocyclyl.
 45. The compound of claim 41, wherein L is CH₂, CHCH₃, CH₂CH₂, or C₃H₆.
 46. The compound of claim 44, wherein L is CH₂, CHCH₃, CH₂CH₂, or C₃H₆.
 47. The compound of claim 41, wherein R³ is C₁₋₆ optionally substituted alkyl substituted with OH or C₂₋₅ optionally substituted heterocyclyl substituted with OH.
 48. The compound of claim 44, wherein R³ is C₁₋₆ optionally substituted alkyl substituted with OH or C₂₋₅ optionally substituted heterocyclyl substituted with OH.
 49. The compound of claim 42 having the formula:

wherein R⁸ and R⁹ are independently H, optionally substituted C₁₋₈ alkyl, optionally substituted C₃₋₅ cycloalkyl, optionally substituted phenyl, optionally substituted C₃₋₅ heterocyclyl, or R⁸ and R⁹ are taken together to comprise a C₃₋₆ cycloalkyl; R⁶ and R⁷ are independently H, CH₃, or CH₂CH₃.
 50. The compound of claim 49, wherein R³ is H, Cl, CH₃, CF₃, CN, C₁₋₅ hydroxyalkyl, O—C₁₋₃ alkyl, O-benzyl, optionally substituted C₃₋₄ cycloalkyl, or morpholino.
 51. The compound of claim 49, wherein R⁴ is H, F, Cl, Br, CN, CH₃, CF₃, cyclopropyl, or OCHF₂.
 52. The compound of claim 49, wherein R⁵ is H, CH₃, CF₃, or OCH₃.
 53. The compound of claim 47 having the formula:

wherein R¹⁰ and R¹¹ are independently H, C₁₋₆ alkyl, or R¹⁰ and R¹¹ are joined by a bond to form a C₃₋₅ heterocyclic ring; R¹² is C₃₋₈ optionally substituted alkyl.
 54. The compound of claim 53, wherein R⁴ is H.
 55. The compound of claim 53, wherein R⁵ is H.
 56. The compound of claim 53, wherein R¹⁰ and R¹¹ are independently H or CH₃, or R¹⁰ and R¹¹ are joined to form a hydroxyoxetane.
 57. The compound of claim 53, wherein R¹² is C₁₋₇ alkyl optionally substituted with: optionally substituted aryl, 1-5 fluorine atoms, or a combination thereof.
 58. A compound represented by a formula:


59. A compound represented by a formula:


60. A method of treating a disorder associated with a Kv7 potassium channel activator comprising administering an effective amount of a compound of claim 41 to a mammal in need thereof, wherein the disorder is epilepsy, pain or migraine.
 61. A method of activating a Kv7 potassium channel comprising administering an effective amount of a compound of claim 41 to a mammal in need thereof. 